Substituted imidazoles as n-type calcium channel blockers

ABSTRACT

Disclosed are compounds, compositions and methods for treating various diseases, syndromes, conditions and disorders, including pain. Such compounds are represented by Formula (I) as follows: 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3 , and G are defined herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/202,600, filed Jul. 6, 2016, which is a divisional of U.S. patentApplication Ser. No. 13/968,480, filed Aug. 16, 2013, each of which ishereby incorporated by reference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

The research and development of the invention described below was notfederally sponsored.

BACKGROUND OF THE INVENTION

Calcium ions play a fundamental role in the physiology and biochemistryof organisms and of cells. The entry of calcium into cells through ionchannels mediates a variety of cellular and physiological responses,including gene expression, signal transduction, neurotransmitterrelease, muscle contraction and hormone secretion. Ion channels areclassified by gating, or what opens and closes the channel to the fluxof ions. Voltage-gated ion channels open or close depending on thevoltage gradient across the plasma membrane, whereas ligand-gated ionchannels open or close depending on the binding of ligands to thechannel. The classification of voltage-gated calcium channels dividesthem into three groups: (i) high voltage-activated channels, whichinclude L-, N-, P- and Q-type channels; (ii) intermediatevoltage-activated R-type channels; and (iii) low voltage-activatedT-type channels.

The N-type calcium channel is distributed mainly in central andperipheral neurons, being localized primarily to presynaptic nerveterminals. This channel regulates the calcium flux required fordepolarization-evoked release of neurotransmitters from synapticendings. The transmission of pain signals from the periphery to thecentral nervous system (CNS) is mediated, inter alia, by N-type calciumchannels located in the spinal cord. Inhibition of the N-type calciumchannel in the superficial dorsal horn leads to a decrease in membraneexcitability and neurotransmitter release, resulting in pain relief. Inaddition, knock-out mice lacking the N-type calcium channel exhibitreduced nociceptive behaviors in animal models of pain.

N-type calcium channels have been shown to mediate the development andmaintenance of the neuronal sensitization processes associated withneuropathic pain and therefore provide attractive targets for thedevelopment of analgesic drugs. Three N-type calcium channel modulatorsare currently approved for the treatment of pain: ω-conotoxin MVIIA(ziconotide), marketed as Prialt®, potently and selectively blocks theN-type calcium channel and is indicated for the management of severechronic pain; gabapentin, marketed as Neurontin®, and pregabalin,marketed as Lyrica®, bind with high affinity to the α2δ subunit of theN-type calcium channel and are indicated for the treatment offibromyalgia, diabetic nerve pain and/or post-herpetic neuralgia pain.

It is an object of the present invention to provide N-Type calciumchannel blockers. It is also an object of the invention to provide amethod of treating, ameliorating or preventing pain by theadministration of a compound of Formula (I). And, it is an object of theinvention to provide a pharmaceutical composition comprising a compoundof Formula (I), useful for treating, ameliorating or preventing pain.

SUMMARY OF THE INVENTION

The present invention is directed to a compound of Formula (I)

wherein

R¹ is

i) phenyl optionally independently substituted with one to threesubstituents that are selected from the group consisting of chloro,fluoro, bromo, cyano, trifluoromethyl, C₁₋₄alkyl, difluoromethoxy, andC₁₋₄alkoxy; provided that when phenyl of group (i) is substituted with asingle substituent, that substituent is at the 4-position;

ii) a heteroaryl selected from the group consisting of pyridinyl,pyrimidinyl, pyridazinyl, and pyrazinyl; wherein said heteroaryl isoptionally independently substituted with one or two substituents thatare chloro, fluoro, bromo, cyano, trifluoromethyl, C₁₋₄alkyl, orC₁₋₄alkoxy;

iii) pyrimidin-5-ylmethyl;

iv) phenylmethyl, wherein the phenyl portion of phenylmethyl isoptionally independently substituted with one or two substituents thatare selected from the group consisting of chloro, fluoro, bromo, cyano,trifluoromethyl, C₁₋₄alkyl, and C₁₋₄alkoxy; provided that whenphenylmethyl of group (iv) is substituted with a single substituent,that substituent is at the 4-position;

v) phenylsulfonyl, wherein the phenyl portion of phenylsulfonyl isoptionally independently substituted with one or two substituents thatare selected from the group consisting of chloro, fluoro, bromo, cyano,trifluoromethyl, C₁₋₄alkyl, and C₁₋₄alkoxy; provided that whenphenylsulfonyl of group (v) is substituted with a single substituent,that substituent is at the 4-position;

vi) C₁₋₄alkylsulfonyl;

vii) C₃₋₇cycloalkylsulfonyl; or

viii) trifluoromethylsulfonyl;

R² is

i) phenyl optionally substituted with a substituent that is selectedfrom the group consisting of C₁₋₄alkoxy and trifluoromethoxy;

ii) a heteroaryl selected from the group consisting of pyridinyl,pyrimidinyl, thiazolyl, triazolyl, and pyrazinyl; wherein saidheteroaryl is optionally substituted with a substituent that isC₁₋₄alkyl, C₁₋₄alkoxy, trifluoromethoxy, or hydroxy;

iii) C₃₋₇cycloalkyl; or

iv) C₃₋₇cycloalkyl-(C₁₋₂)alkyl;

R³ is selected from the group consisting of hydrogen ,chloro, andmethyl;

G is G1, G2, or G3,

and enantiomers, diastereomers, solvates and pharmaceutically acceptablesalts thereof.

The present invention also provides, inter alia, a pharmaceuticalcomposition comprising, consisting of and/or consisting essentially of apharmaceutically acceptable carrier, a pharmaceutically acceptableexcipient, and/or a pharmaceutically acceptable diluent, and a compoundof Formula (I), or a pharmaceutically acceptable salt form thereof.

Also provided are processes for making a pharmaceutical compositioncomprising, consisting of, and/or consisting essentially of admixing acompound of Formula (I) and a pharmaceutically acceptable carrier, apharmaceutically acceptable excipient, and/or a pharmaceuticallyacceptable diluent.

The present invention further provides, inter alia, methods for treatingor ameliorating a N-Type calcium channel-modulated disorder in asubject, including a human or other mammal in which the disease,syndrome, or condition is affected by the modulation of the N-Typecalcium channel, such as pain and the diseases that lead to such pain,using a compound of Formula (I).

The present invention also provides, inter alia, methods for producingthe instant compounds and pharmaceutical compositions and medicamentsthereof.

DETAILED DESCRIPTION OF THE INVENTION

With reference to substituents, the term “independently” refers to thesituation where when more than one substituent is possible, thesubstituents may be the same or different from each other.

The term “alkyl” whether used alone or as part of a substituent group,refers to straight and branched carbon chains having 1 to 8 carbonatoms. Therefore, designated numbers of carbon atoms (e.g. C₁₋₈) referindependently to the number of carbon atoms in an alkyl moiety or to thealkyl portion of a larger alkyl-containing substituent. In substituentgroups with multiple alkyl groups such as (C₁₋₆alkyl)₂amino-, theC₁₋₆alkyl groups of the dialkylamino may be the same or different.

The term “alkoxy” refers to an —O-alkyl group, wherein the term “alkyl”is as defined above.

The terms “alkenyl” and “alkynyl” refer to straight and branched carbonchains having 2 or more carbon atoms, wherein an alkenyl chain containsat least one double bond and an alkynyl chain contains at least onetriple bond.

The term “cycloalkyl” refers to saturated or partially saturated,monocyclic or polycyclic hydrocarbon rings of 3 to 14 carbon atoms.Examples of such rings include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and adamantyl.

The term “benzo-fused cycloalkyl” refers to a 5- to 8-memberedmonocyclic cycloalkyl ring fused to a benzene ring. The carbon atom ringmembers that form the cycloalkyl ring may be fully saturated orpartially saturated.

The term “heterocyclyl” refers to a nonaromatic monocyclic or bicyclicring system having 3 to 10 ring members and which contains carbon atomsand from 1 to 4 heteroatoms independently selected from the groupconsisting of N, O, and S. Included within the term heterocyclyl is anonaromatic cyclic ring of 5 to 7 members in which 1 to 2 members arenitrogen, or a nonaromatic cyclic ring of 5 to 7 members in which 0, 1or 2 members are nitrogen and up to 2 members are oxygen or sulfur andat least one member must be either nitrogen, oxygen or sulfur; wherein,optionally, the ring contains zero to one unsaturated bonds, and,optionally, when the ring is of 6 or 7 members, it contains up to 2unsaturated bonds. The carbon atom ring members that form a heterocyclering may be fully saturated or partially saturated. The term“heterocyclyl” also includes two 5 membered monocyclic heterocycloalkylgroups bridged to form a bicyclic ring. Such groups are not consideredto be fully aromatic and are not referred to as heteroaryl groups.

When a heterocycle is bicyclic, both rings of the heterocycle arenon-aromatic and at least one of the rings contains a heteroatom ringmember. Examples of heterocycle groups include, and are not limited to,pyrrolinyl (including 2H-pyrrole, 2-pyrrolinyl or 3-pyrrolinyl),pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl. Unlessotherwise noted, the heterocycle is attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure.

The term “benzo-fused heterocyclyl” refers to a 5 to 7 memberedmonocyclic heterocycle ring fused to a benzene ring. The heterocyclering contains carbon atoms and from 1 to 4 heteroatoms independentlyselected from the group consisting of N, O, and S. The carbon atom ringmembers that form the heterocycle ring may be fully saturated orpartially saturated. Unless otherwise noted, benzo-fused heterocyclering is attached to its pendant group at a carbon atom of the benzenering.

The term “aryl” refers to an unsaturated, aromatic monocyclic orbicyclic ring of 6 to 10 carbon members. Examples of aryl rings includephenyl and naphthalenyl.

The term “heteroaryl” refers to an aromatic monocyclic or bicyclicaromatic ring system having 5 to 10 ring members and which containscarbon atoms and from 1 to 4 heteroatoms independently selected from thegroup consisting of N, O, and S. Included within the term heteroaryl arearomatic rings of 5 or 6 members wherein the ring consists of carbonatoms and has at least one heteroatom member. Suitable heteroatomsinclude nitrogen, oxygen, and sulfur. In the case of 5 membered rings,the heteroaryl ring preferably contains one member of nitrogen, oxygenor sulfur and, in addition, up to 3 additional nitrogens. In the case of6 membered rings, the heteroaryl ring preferably contains from 1 to 3nitrogen atoms. For the case wherein the 6 membered ring has 3nitrogens, at most 2 nitrogen atoms are adjacent. Examples of heteroarylgroups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl,isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl,benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzothiadiazolyl,benzotriazolyl, quinolinyl, isoquinolinyl and quinazolinyl. Unlessotherwise noted, the heteroaryl is attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure.

The term “halogen” or “halo” refers to fluorine, chlorine, bromine andiodine.

The term “formyl” refers to the group —C(═O)H.

The term “oxo” refers to the group (═O).

Whenever the term “alkyl” or “aryl” or either of their prefix rootsappear in a name of a substituent (e.g., arylalkyl, alkylamino) the nameis to be interpreted as including those limitations given above for“alkyl” and “aryl.” Designated numbers of carbon atoms (e.g., C₁-C₆)refer independently to the number of carbon atoms in an alkyl moiety, anaryl moiety, or in the alkyl portion of a larger substituent in whichalkyl appears as its prefix root. For alkyl and alkoxy substituents, thedesignated number of carbon atoms includes all of the independentmembers included within a given range specified. For example C₁₋₆alkylwould include methyl, ethyl, propyl, butyl, pentyl and hexylindividually as well as sub-combinations thereof (e.g., C₁₋₂, C₁₋₃,C₁₋₄, C₁₋₅, C₂₋₆, C₃₋₆, C₄₋₆, C₅₋₆, C₂₋₅, etc.).

In general, under standard nomenclature rules used throughout thisdisclosure, the terminal portion of the designated side chain isdescribed first followed by the adjacent functionality toward the pointof attachment. Thus, for example, a “C₁-C₆ alkylcarbonyl” substituentrefers to a group of the formula:

The term “R” at a stereocenter designates that the stereocenter ispurely of the R-configuration as defined in the art; likewise, the term“S” means that the stereocenter is purely of the S-configuration. Asused herein, the terms “*R” or “*S” at a stereocenter are used todesignate that the stereocenter is of pure but unknown configuration. Asused herein, the term “RS” refers to a stereocenter that exists as amixture of the R- and S-configurations. Similarly, the terms “*RS” or“*SR” refer to a stereocenter that exists as a mixture of the R- andS-configurations and is of unknown configuration relative to anotherstereocenter within the molecule.

Compounds containing one stereocenter drawn without a stereo bonddesignation are a mixture of two enantiomers. Compounds containing twostereocenters both drawn without stereo bond designations are a mixtureof 4 diastereomers. Compounds with 2 stereocenters both labeled “RS” anddrawn with stereo bond designations are a 2-component mixture withrelative stereochemistry as drawn. Compounds with 2 stereocenters bothlabeled “*RS” and drawn with stereo bond designations are a 2-componentmixture with relative stereochemistry unknown. Unlabeled stereocentersdrawn without stereo bond designations are a mixture of the R- andS-configurations. For unlabeled stereocenters drawn with stereo bonddesignations, the absolute stereochemistry is as depicted.

Unless otherwise noted, it is intended that the definition of anysubstituent or variable at a particular location in a molecule beindependent of its definitions elsewhere in that molecule. It isunderstood that substituents and substitution patterns on the compoundsof Formula (I) can be selected by one of ordinary skill in the art toprovide compounds that are chemically stable and that can be readilysynthesized by techniques known in the art as well as those methods setforth herein.

The term “subject” refers to an animal, preferably a mammal, mostpreferably a human, who has been the object of treatment, observation orexperiment.

The term “therapeutically effective amount” refers to an amount of anactive compound or pharmaceutical agent, including a compound of thepresent invention, which elicits the biological or medicinal response ina tissue system, animal or human that is being sought by a researcher,veterinarian, medical doctor or other clinician, which includesalleviation or partial alleviation of the symptoms of the disease,syndrome, condition, or disorder being treated.

The term “composition” refers to a product that includes the specifiedingredients in therapeutically effective amounts, as well as any productthat results, directly, or indirectly, from combinations of thespecified ingredients in the specified amounts.

The term “N-Type calcium channel blocker” is intended to encompass acompound that interacts with the N-Type calcium channel to substantiallyreduce or eliminate its functional activity, thereby decreasing the flowof calcium ions through the channel and the rise of intracellularcalcium concentrations.

The term “N-Type calcium channel-modulated” is used to refer to thecondition of being affected by the modulation of the N-Type calciumchannel, including the condition of being affected by the inhibition ofthe N-Type calcium channel, such as, for example, pain, the diseasesthat lead to such pain and treatments that lead to the reduction of suchpain.

As used herein, unless otherwise noted, the term “affect” or “affected”(when referring to a disease, syndrome, condition or disorder that isaffected by the inhibition of N-Type calcium channel) shall include areduction in the frequency and/or severity of one or more symptoms ormanifestations of said disease, syndrome, condition or disorder and/orinclude the prevention of the development of one or more symptoms ormanifestations of said disease, syndrome, condition or disorder or thedevelopment of the disease, condition, syndrome or disorder.

The compounds of Formula (I) are useful in methods for treating,ameliorating and/or preventing a disease, a syndrome, a condition or adisorder that is affected by the inhibition of N-Type calcium channel.Such methods comprise, consist of and/or consist essentially ofadministering to a subject, including an animal, a mammal, and a humanin need of such treatment, amelioration and/or prevention, atherapeutically effective amount of a compound of Formula (I), or anenantiomer, diastereomer, solvate or pharmaceutically acceptable saltform thereof. In particular, the compounds of Formula (I) are useful fortreating, ameliorating and/or preventing pain as well as diseases,syndromes, conditions or disorders causing such pain. More particularly,the compounds of Formula (I) are useful for treating, amelioratingand/or preventing acute pain, inflammatory pain and/or neuropathic pain,comprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound of Formula (I), as herein defined.

Acute pain, as used herein, refers to pain that comes on quickly, can beof varying severity but is self-limiting and of relatively shortduration. Examples of acute pain include, but are not limited to,post-operative pain, post-surgical pain, toothache, burn, sunburn,insect/animal bites and stings, headache and/or any pain associated withacute trauma or injury.

Inflammatory pain refers to pain arising from an inflammatory disease,condition, syndrome or disorder, including but not limited toinflammatory bowel disease, irritable bowel sysdrome, visceral pain,migraine, post-operative pain, osteoarthritis, rheumatoid arthritis,back pain, low back pain, joint pain, abdominal pain, chest pain, laborpain, musculoskeletal diseases, skin diseases, toothache, pyresis, burn,sunburn, snake bite, venomous snake bite, spider bite, insect sting,neurogenic or overactive bladder, interstitial cystitis, urinary tractinfection, rhinitis, contact dermatitis/hypersensitivity, itch, eczema,pharyngitis, mucositis, enteritis, irritable bowel syndrome,cholecystitis, pancreatitis, post-mastectomy pain syndrome, menstrualpain, endometriosis, pain due to physical trauma, headache, sinusheadache, tension headache or arachnoiditis.

A further embodiment of the present invention is directed to a methodfor treating, ameliorating and/or preventing neuropathic pain.Neuropathic pain refers to a disease, syndrome, condition and/ordisorder involving damage to the peripheral or central nervous system,including cancer pain, neurological disorders, spine and peripheralnerve surgery, brain tumor, traumatic brain injury (TBI),chemotherapy-induced pain, pain chronification, radicular pain, HIVpain, spinal cord trauma, chronic pain syndrome, fibromyalgia, chronicfatigue syndrome, lupus, sarcoidosis, peripheral neuropathy, bilateralperipheral neuropathy, diabetic neuropathy, central pain, neuropathiesassociated with spinal cord injury, stroke, amyotrophic lateralsclerosis (ALS), Parkinson's disease, multiple sclerosis, sciaticneuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis,stump pain, phantom limb pain, bony fractures, oral neuropathic pain,Charcot's pain, complex regional pain syndrome I and II (CRPS I/II),radiculopathy, Guillain-Barre syndrome, meralgia paresthetica,burning-mouth syndrome, optic neuritis, postfebrile neuritis, migratingneuritis, segmental neuritis, Gombault's neuritis, neuronitis,cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia,glossopharyngial neuralgia, migrainous neuralgia, idiopathic neuralgia,intercostals neuralgia, mammary neuralgia, Morton's neuralgia,nasociliary neuralgia, occipital neuralgia, post-herpetic neuralgia,causalgia, red neuralgia, Sluder's neuralgia, splenopalatine neuralgia,supraorbital neuralgia, trigeminal neuralgia, vulvodynia, or vidianneuralgia.

Embodiments of the present invention include a compound of Formula (I)

wherein

-   a) R¹ is    -   i) phenyl independently substituted with one to three        substituents that are selected from the group consisting of        chloro, fluoro, bromo, cyano, trifluoromethyl, C₁₋₄alkyl,        difluoromethoxy, and C₁₋₄alkoxy; provided that when phenyl of        group (i) is substituted with a single substituent, that        substituent is at the 4-position;    -   ii) a heteroaryl that is pyridinyl; wherein said pyridinyl is        optionally independently substituted with one or two        substituents that are chloro, fluoro, bromo, cyano,        trifluoromethyl, C₁₋₄alkyl, or C₁₋₄alkoxy;    -   iii) phenylmethyl, wherein the phenyl portion of phenylmethyl is        optionally independently substituted with one or two        substituents that are selected from the group consisting of        chloro, fluoro, bromo, cyano, trifluoromethyl, C₁₋₄alkyl, and        C₁₋₄alkoxy; provided that when phenylmethyl of group (iii) is        substituted with a single substituent, that substituent is at        the 4-position;    -   iv) phenylsulfonyl, wherein the phenyl portion of phenylsulfonyl        is optionally independently substituted with one or two        substituents that are selected from the group consisting of        chloro, fluoro, bromo, cyano, trifluoromethyl, C₁₋₄alkyl, and        C₁₋₄alkoxy; provided that when phenylsulfonyl of group (iv) is        substituted with a single substituent, that substituent is at        the 4-position;    -   v) C₁₋₄alkylsulfonyl;    -   or    -   vi) trifluoromethylsulfonyl;-   b) R¹ is    -   i) phenyl independently substituted with one to three        substituents that are selected from the group consisting of        chloro, fluoro, bromo, cyano, trifluoromethyl, methyl,        difluoromethoxy, and C₁₋₂alkoxy; provided that when phenyl of        group (i) is substituted with a single substituent, that        substituent is at the 4-position; or    -   ii) a heteroaryl that is pyridinyl; wherein said pyridinyl is        optionally independently substituted with one or two        substituents that are chloro, fluoro, bromo, cyano,        trifluoromethyl, or C₁₋₄alkoxy;-   c) R¹ is phenyl independently substituted with one to three    substituents that are selected from the group consisting of chloro,    fluoro, cyano, trifluoromethyl, difluoromethoxy, and methyl;    provided that when phenyl is substituted with a single substituent,    that substituent is at the 4-position;-   d) R² is    -   i) phenyl substituted with a substituent that is selected from        the group consisting of C₁₋₄alkoxy and trifluoromethoxy;    -   ii) a heteroaryl selected from the group consisting of        pyridinyl, pyrimidinyl, and pyrazinyl; wherein said heteroaryl        is optionally substituted with a substituent that is C₁₋₄alkoxy        or trifluoromethoxy;    -   iii) C₃₋₇cycloalkyl; or    -   iv) C₃₋₇cycloalkyl-(C₁₋₂)alkyl;-   e) R² is    -   i) phenyl substituted with C₁₋₄alkoxy;    -   ii) a heteroaryl selected from the group consisting of pyridinyl        and pyrazinyl; wherein said heteroaryl is optionally substituted        with C₁₋₄alkoxy; or    -   iii) C₃₋₇cycloalkyl-(C₁₋₂)alkyl;-   f) R² is    -   i) phenyl substituted with C₁₋₄alkoxy; or    -   ii) a heteroaryl selected from the group consisting of pyridinyl        and pyrazinyl; wherein said heteroaryl is optionally substituted        with C₁₋₄alkoxy;-   g) R² is    -   i) phenyl substituted with methoxy; or    -   ii) a heteroaryl selected from the group consisting of pyridinyl        and pyrazinyl; wherein said heteroaryl is optionally substituted        with C₁₋₂alkoxy;-   h) R³ is hydrogen;-   i) G is G1 or G2;

-   j) G is G1;

-   k) G is G2;

and any combination of embodiments a) through k) above, provided that itis understood that combinations in which different embodiments of thesame substituent would be combined are excluded;

and enantiomers, diastereomers, solvates and pharmaceutically acceptablesalts thereof.

An embodiment of the present invention is directed to a compound ofFormula (I)

wherein

R¹ is

-   -   i) phenyl independently substituted with one to three        substituents that are selected from the group consisting of        chloro, fluoro, bromo, cyano, trifluoromethyl, C₁₋₄alkyl,        difluoromethoxy, and C₁₋₄alkoxy; provided that when phenyl of        group (i) is substituted with a single substituent, that        substituent is at the 4-position;    -   ii) a heteroaryl that is pyridinyl; wherein said pyridinyl is        optionally independently substituted with one or two        substituents that are chloro, fluoro, bromo, cyano,        trifluoromethyl, C₁₋₄alkyl, or C₁₋₄alkoxy;    -   iii) phenylmethyl, wherein the phenyl portion of phenylmethyl is        optionally independently substituted with one or two        substituents that are selected from the group consisting of        chloro, fluoro, bromo, cyano, trifluoromethyl, C₁₋₄alkyl, and        C₁₋₄alkoxy; provided that when phenylmethyl of group (iii) is        substituted with a single substituent, that substituent is at        the 4-position;    -   iv) phenylsulfonyl, wherein the phenyl portion of phenylsulfonyl        is optionally independently substituted with one or two        substituents that are selected from the group consisting of        chloro, fluoro, bromo, cyano, trifluoromethyl, C₁₋₄alkyl, and        C₁₋₄alkoxy; provided that when phenylsulfonyl of group (iv) is        substituted with a single substituent, that substituent is at        the 4-position;    -   v) C₁₋₄alkylsulfonyl; or    -   vi) trifluoromethylsulfonyl;

R² is

-   -   i) phenyl substituted with a substituent that is selected from        the group consisting of C₁₋₄alkoxy and trifluoromethoxy;    -   ii) a heteroaryl selected from the group consisting of        pyridinyl, pyrimidinyl, and pyrazinyl; wherein said heteroaryl        is optionally substituted with a substituent that is C₁₋₄alkoxy        or trifluoromethoxy;    -   iii) C₃₋₇cycloalkyl; or    -   iv) C₃₋₇cycloalkyl-(C₁₋₂)alkyl;

R³ is hydrogen, chloro, or methyl;

G is G1 or G2;

and enantiomers, diastereomers, solvates, and pharmaceuticallyacceptable salt forms thereof.

An embodiment of the present invention is directed to a compound ofFormula (I)

wherein

R¹ is

-   -   i) phenyl independently substituted with one to three        substituents that are selected from the group consisting of        chloro, fluoro, bromo, cyano, trifluoromethyl, methyl,        difluoromethoxy, and C₁₋₂alkoxy; provided that when phenyl of        group (i) is substituted with a single substituent, that        substituent is at the 4-position; or    -   ii) a heteroaryl that is pyridinyl; wherein said pyridinyl is        optionally independently substituted with one or two        substituents that are chloro, fluoro, bromo, cyano,        trifluoromethyl, or C₁₋₄alkoxy;

R² is

-   -   i) phenyl substituted with C₁₋₄alkoxy;    -   ii) a heteroaryl selected from the group consisting of pyridinyl        and pyrazinyl; wherein said heteroaryl is optionally substituted        with C₁₋₄alkoxy; or    -   iii) C₃₋₇cycloalkyl-(C₁₋₂)alkyl;

R³ is hydrogen;

G is G1 or G2;

and enantiomers, diastereomers, solvates, and pharmaceuticallyacceptable salt forms thereof.

An embodiment of the present invention is directed to a compound ofFormula (I)

wherein

R¹ is phenyl independently substituted with one to three substituentsthat are selected from the group consisting of chloro, fluoro, cyano,trifluoromethyl, difluoromethoxy, and methyl; provided that when phenylis substituted with a single substituent, that substituent is at the4-position;

R² is

-   -   i) phenyl substituted with C₁₋₄alkoxy; or    -   ii) a heteroaryl selected from the group consisting of pyridinyl        and pyrazinyl; wherein said heteroaryl is optionally substituted        with C₁₋₄alkoxy;

R³ is hydrogen;

G is G1 or G2;

and enantiomers, diastereomers, solvates, and pharmaceuticallyacceptable salt forms thereof.

An embodiment of the present invention is directed to a compound ofFormula (I)

wherein

R¹ is phenyl independently substituted with one to three substituentsthat are selected from the group consisting of chloro, fluoro, cyano,trifluoromethyl, difluoromethoxy, and methyl; provided that when phenylis substituted with a single substituent, that substituent is at the4-position;

R² is

-   -   i) phenyl substituted with methoxy; or    -   ii) a heteroaryl selected from the group consisting of pyridinyl        and pyrazinyl; wherein said heteroaryl is optionally substituted        with C₁₋₂alkoxy;

R³ is hydrogen;

G is G1 or G2;

and enantiomers, diastereomers, solvates, and pharmaceuticallyacceptable salt forms thereof.

An embodiment of the present invention is directed to a compound ofFormula (I)

wherein

R¹ is phenyl independently substituted with one to three substituentsthat are selected from the group consisting of chloro, fluoro, cyano,trifluoromethyl, difluoromethoxy, and methyl; provided that when phenylis substituted with a single substituent, that substituent is at the4-position;

R² is

-   -   i) phenyl substituted with methoxy; or    -   ii) a heteroaryl selected from the group consisting of pyridinyl        and pyrazinyl; wherein said heteroaryl is optionally substituted        with C₁₋₂alkoxy;

R³ is hydrogen;

G is G1;

and enantiomers, diastereomers, solvates, and pharmaceuticallyacceptable salt forms thereof.

An embodiment of the present invention is directed to a compound ofFormula (I)

wherein

R¹ is phenyl independently substituted with one to three substituentsthat are selected from the group consisting of chloro, fluoro, cyano,trifluoromethyl, difluoromethoxy, and methyl; provided that when phenylis substituted with a single substituent, that substituent is at the4-position;

R² is

-   -   i) phenyl substituted with methoxy; or    -   ii) a heteroaryl selected from the group consisting of pyridinyl        and pyrazinyl; wherein said heteroaryl is optionally substituted        with C₁₋₂alkoxy;

R³ is hydrogen;

G is G2;

and enantiomers, diastereomers, solvates, and pharmaceuticallyacceptable salt forms thereof.

Further embodiments of the present invention are directed to a compoundof Formula (I)

selected from the group consisting of

-   Cpd 1,    4-[2-(2-Methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]benzonitrile;-   Cpd 2,    4-[1-(4-Fluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-3-methoxypyridine;-   Cpd 3,    2-Ethoxy-5-[2-(3-methoxypyridin-4-yl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]pyridine;-   Cpd 4,    1-(4-Fluorophenyl)-2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole;-   Cpd 5,    5-[2-(2-Methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]-2-methylpyridine;-   Cpd 6,    2-[2-(2-Methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]-5-methylpyridine;-   Cpd 7,    2-(2-Methoxyphenyl)-1-(4-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole;-   Cpd 8,    5-[2-(2-Methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]-2-methylpyrimidine;-   Cpd 9,    3-(1-(3-chlorobenzyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)-2-methoxypyridine;-   Cpd 10, 3-    [1-(4-Fluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine;-   Cpd 11, 3-    [1-(4-Chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine;-   Cpd 12,    4-[2-(3-Methoxypyridin-2-yl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]benzonitrile;-   Cpd 13, 4-    [1-(4-Chloro-3-fluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-3-methoxypyridine;-   Cpd 14, 2-Chloro-5-    [2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]benzonitrile;-   Cpd 15,    4-[2-(2-Methoxypyridin-3-yl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]-2-methylbenzonitrile;-   Cpd, 16,    2-methoxy-3-(4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1-(2,3,4-trifluorophenyl)-1H-imidazol-2-yl)pyridine;-   Cpd 17, 2-    [1-(3-Chloro-4-fluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-3-methoxypyridine;-   Cpd 18, 4-    [1-(3-Chloro-4-fluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-3-methoxypyridine;-   Cpd 19, 2-    [1-(4-Chloro-3-fluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-3-methoxypyridine;-   Cpd 20, 3-    [1-(3-Chloro-4-fluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-4-methoxypyridine;-   Cpd 21, 4-    [2-(2-Methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]-2-methylbenzonitrile;-   Cpd 22, 5-    [2-(2-Methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]-2-methylbenzonitrile;-   Cpd 23, 3-    [1-(3-Fluoro-4-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine;-   Cpd 24, 3-    [1-(4-Fluoro-3-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine;-   Cpd 25,    5-[2-(2-Methoxypyridin-3-yl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]-2-methylbenzonitrile;-   Cpd 26, 3-    [1-(4-Chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-4-methyl-4H-1,2,4-triazole;-   Cpd 27, 3-    [1-(2-Chlorobenzyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine;-   Cpd 28, 3-    [1-(4-Chlorobenzyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine;-   Cpd 29,    4-(2-(2-methoxypyridin-3-yl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl)-2-(trifluoromethyl)benzonitrile;-   Cpd 30, 3-    [1-(2,4-Difluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine;-   Cpd 31,    3-(1-(2,3-difluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)-2-methoxypyridine;-   Cpd 32, 3-    [2-(2-Methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]benzonitrile;-   Cpd 33, 4- [1-(3    ,4-Difluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-3-methoxypyridine;-   Cpd 34,    2-Methoxy-4-[2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]benzonitrile;-   Cpd 35, 2-    [1-(3,4-Difluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-3-methoxypyridine;-   Cpd 36, 3-Fluoro-4-    [2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]benzonitrile;-   Cpd 37,    2-Methoxy-5-[2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]benzonitrile;-   Cpd 38,    1-(4-Chlorophenyl)-2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole;-   Cpd 39,    5-Chloro-2-[2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]pyridine;-   Cpd 40,    3-[1-(3,4-Difluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine;-   Cpd 41,    1-(4-Chloro-3-fluorophenyl)-2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole;-   Cpd 42,    1-(3,4-Difluorophenyl)-2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole;-   Cpd 43,    4-[2-(2-Methoxypyridin-3-yl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]benzonitrile;-   Cpd 44,    3-[1-(4-Chloro-3-fluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine;-   Cpd 45,    1-(3-Chloro-4-fluorophenyl)-2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole;-   Cpd 46,    3-[1-(3-Chloro-4-fluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine;-   Cpd 47,    2-[1-(4-Fluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-3-methoxypyrazine;-   Cpd 48,    3-[2-(2-Methoxypyridin-3-yl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]benzonitrile;-   Cpd 49, 5-    [1-(4-Chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-4-methoxypyrimidine;-   Cpd 50,    2-[1-(4-Chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-3-methoxypyrazine;-   Cpd 51, 3-    [1-(4-Chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-ethoxypyridine;-   Cpd 52,    3-[1-(3,4-Difluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-ethoxypyridine;    Cpd 53,    5-[2-(2-Methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]-2-(trifluoromethyl)pyridine;-   Cpd 54,    2-Methoxy-3-{4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1-    [6-(trifluoromethyl)pyridin-3-yl]-1H-imidazol-2-yl}pyridine;-   Cpd 55,    1-(4-Chlorophenyl)-2-(cyclopropylmethyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole;-   Cpd 56,    1-(4-Chlorophenyl)-2-cyclopropyl-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole;-   Cpd 57,    4-[2-Cyclopropyl-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]benzonitrile;-   Cpd 58,    4-[2-(Cyclopropylmethyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]benzonitrile;-   Cpd 59,    5-[2-(Cyclopropylmethyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]-2-(trifluoromethyl)pyridine;    Cpd 60,    2-[1-(4-Chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-3-ethoxypyrazine;-   Cpd 61,    1-(4-(difluoromethoxy)phenyl)-2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole;-   Cpd 62,    1-(4-Bromo-3-fluorophenyl)-2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole;-   Cpd 63,    1-(3-Bromo-4-fluorophenyl)-2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole;-   Cpd 64,    3-[1-(3-Bromo-4-fluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine;-   Cpd 65,    3-[1-(4-Bromo-3-fluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine;-   Cpd 66,    4-(1-(4-chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)-3-methoxypyridine;-   Cpd 67,    2-(1-(4-chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)-3-methoxypyridine;-   Cpd 68,    3-(1-(4-chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)-4-methoxypyridine;-   Cpd 69,    3-(1-(4-fluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)-4-methoxypyridine;-   Cpd 70,    2-(1-(4-fluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)-3-methoxypyridine;-   Cpd 71,    3-(1-(2,5-difluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)-2-methoxypyridine;-   Cpd 72,    3-(1-(3,5-difluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)-2-methoxypyridine;-   Cpd 73,    3-fluoro-5-(2-(2-methoxypyridin-3-yl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl)benzonitrile;-   Cpd 74,    2-Fluoro-5-[2-(2-methoxy-phenyl)-4-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-imidazol-1-yl]-benzonitrile;-   Cpd 75, 3-    [1-(6-Ethoxypyridin-3-yl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine;-   Cpd 76,    3-Fluoro-4-[2-(2-methoxypyridin-3-yl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]benzonitrile;-   Cpd 77,    2-Methoxy-[2-(2-methoxypyridin-3-yl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]benzonitrile;-   Cpd 78,    2-Chloro-4-[2-(2-methoxypyridin-3-yl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]benzonitrile;-   Cpd 79,    2-Fluoro-5-[2-(2-methoxypyridin-3-yl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]benzonitrile;-   Cpd 80, 2-Fluoro-4-    [2-(2-methoxypyridin-3-yl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]benzonitrile;-   Cpd 81, 2-Fluoro-4-    [2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]benzonitrile;-   Cpd 82,    2,6-difluoro-4-(2-(2-methoxypyridin-3-yl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl)benzonitrile;-   Cpd 83, 3    ,5-difluoro-4-(2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl)benzonitrile;-   Cpd 84, 2-Chloro-5- [2-(2-methoxypyridin-3    -yl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]benzonitrile;-   Cpd 85,    2-Methoxy-5-[2-(2-methoxypyridin-3-yl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]benzonitrile;-   Cpd 86, 4-    [2-(4-Methoxypyrimidin-5-yl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]benzonitrile;-   Cpd 87, 4-    [2-(3-Methoxypyrazin-2-yl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]benzonitrile;-   Cpd 88,    2-fluoro-4-(2-(3-methoxypyrazin-2-yl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl)benzonitrile;-   Cpd 89, 4-(2-(2-ethoxypyridin-3    -yl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl)-2-fluorobenzonitrile;-   Cpd 90,    1-(4-chlorophenyl)-2-(2-methoxyphenyl)-5-methyl-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole;-   Cpd 91, 4-    [5-Chloro-2-(2-methoxypyridin-3-yl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]benzonitrile;-   Cpd 92, 3-    [5-Chloro-1-(4-fluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine;-   Cpd 93, 3-    [5-Chloro-1-(4-chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine;-   Cpd 94,    2-(2-Methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1-[(trifluoromethyl)sulfonyl]-1H-imidazole;-   Cpd 95,    1-(Cyclopropylsulfonyl)-2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole;-   Cpd 96, 2-(2-Methoxyphenyl)-1-    [(2-methylpropyl)sulfonyl]-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole;-   Cpd 97, 1-    [(4-Chlorophenyl)sulfonyl]-2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole;-   Cpd 98, 1-    [(4-Fluorophenyl)sulfonyl]-2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole;-   Cpd 99,    4-{[2-(2-Methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]methyl}benzonitrile;-   Cpd 100,    5-{[2-(2-Methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]methyl}pyrimidine;-   Cpd 101,    3-{[2-(2-Methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]methyl}benzonitrile;-   Cpd 102, 4-    [1-(4-Chlorophenyl)-2-(2-methoxyphenyl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol;-   Cpd 103, 4-    [1-(4-Chlorophenyl)-2-(4-methoxypyridin-3-yl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol;-   Cpd 104, 4-    [1-(4-Chlorophenyl)-2-(3-methoxypyridin-2-yl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol;-   Cpd 105, 4-    [1-(4-Chlorophenyl)-2-(2-methoxypyridin-3-yl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol;-   Cpd 106, 4-    [1-(3-Bromo-4-fluorophenyl)-2-(2-methoxyphenyl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol;-   Cpd 107, 4-    [1-(3,4-Difluorophenyl)-2-(2-methoxyphenyl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol;-   Cpd 108, 4-    [1-(3,4-Difluorophenyl)-2-(2-methoxypyridin-3-yl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol;-   Cpd 109,    4-{2-(2-Methoxyphenyl)-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-imidazol-4-yl}-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol;-   Cpd 110, 4-    [1-(3-Chloro-4-fluorophenyl)-2-(2-methoxypyridin-3-yl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol;-   Cpd 111, 4-    [1-(3-Chloro-4-fluorophenyl)-2-(2-methoxyphenyl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol;-   Cpd 112, 4-    [1-(4-Chloro-3-fluorophenyl)-2-(2-methoxyphenyl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol;-   Cpd 113, 4-    [1-(4-Chloro-3-fluorophenyl)-2-(2-methoxypyridin-3-yl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol;-   Cpd 114, 4-    [1-(4-Chlorophenyl)-2-(2-ethoxypyridin-3-yl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol;-   Cpd 115, 4-    [4-(4-Hydroxy-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-2-(2-methoxypyridin-3-yl)-1H-imidazol-1-yl]benzonitrile;-   Cpd 116,    2-Fluoro-5-[4-(4-hydroxy-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-2-(2-methoxypyridin-3-yl)-1H-imidazol-1-yl]benzonitrile;-   Cpd 117, 2-Fluoro-5-    [4-(4-hydroxy-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-2-(2-methoxyphenyl)-1H-imidazol-1-yl]benzonitrile;-   Cpd 118,    2-Fluoro-4-[4-(4-hydroxy-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-2-(2-methoxyphenyl)-1H-imidazol-1-yl]benzonitrile;-   Cpd 119,    2-Fluoro-4-[4-(4-hydroxy-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-2-(2-methoxypyridin-3-yl)-1H-imidazol-1-yl]benzonitrile;-   Cpd 120, 4-    [1-(4-Chlorophenyl)-2-(3-methoxypyridin-4-yl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol;-   Cpd 121, 4-    [2-(2-Methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]-2-(trifluoromethyl)benzonitrile;-   Cpd 122,    3-[1-(4-Chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]pyridin-2-ol;-   Cpd 123 ,    2-Chloro-4-[2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]benzonitrile;-   Cpd 124,    1-(4-Chlorophenyl)-2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl)-1H-imidazole;-   Cpd 125,    1-(4-Bromo-3-fluorophenyl)-2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl)-1H-imidazole;-   Cpd 126,    2-Fluoro-4-[2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl)-1H-imidazol-1-yl]benzonitrile;    and pharmaceutically acceptable salt forms thereof.

For use in medicine, salts of compounds of Formula (I) refer tonon-toxic “pharmaceutically acceptable salts.” Other salts may, however,be useful in the preparation of compounds of Formula (I) or of theirpharmaceutically acceptable salts thereof. Suitable pharmaceuticallyacceptable salts of compounds of Formula (I) include acid addition saltswhich can, for example, be formed by mixing a solution of the compoundwith a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of Formula (I)carry an acidic moiety, suitable pharmaceutically acceptable saltsthereof may include alkali metal salts, such as sodium or potassiumsalts; alkaline earth metal salts, such as calcium or magnesium salts;and salts formed with suitable organic ligands, such as quaternaryammonium salts. Thus, representative pharmaceutically acceptable saltsinclude acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,tosylate, triethiodide and valerate.

Representative acids and bases that may be used in the preparation ofpharmaceutically acceptable salts include acids including acetic acid,2,2-dichloroactic acid, acylated amino acids, adipic acid, alginic acid,ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaricacid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronicacid, L-glutamic acid, a-oxo-glutaric acid, glycolic acid, hippuricacid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid,(±)-DL-lactic acid, lactobionic acid, maleic acid, (−)-L-malic acid,malonic acid, (±)-DL-mandelic acid, methanesulfonic acid,naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid,orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid,L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaicacid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid andundecylenic acid; and bases including ammonia, L-arginine, benethamine,benzathine, calcium hydroxide, choline, deanol, diethanolamine,diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide,triethanolamine, tromethamine and zinc hydroxide.

Embodiments of the present invention include prodrugs of compounds ofFormula (I). In general, such prodrugs will be functional derivatives ofthe compounds that are readily convertible in vivo into the requiredcompound. Thus, in the methods of treating or preventing embodiments ofthe present invention, the term “administering” encompasses thetreatment or prevention of the various diseases, conditions, syndromesand disorders described with the compound specifically disclosed or witha compound that may not be specifically disclosed, but which converts tothe specified compound in vivo after administration to a patient.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in “Design of Prodrugs”,ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to embodiments of this invention have atleast one chiral center, they may accordingly exist as enantiomers.Where the compounds possess two or more chiral centers, they mayadditionally exist as diastereomers. It is to be understood that allsuch isomers and mixtures thereof are encompassed within the scope ofthe present invention. Furthermore, some of the crystalline forms forthe compounds may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compoundsmay form solvates with water (i.e., hydrates) or common organicsolvents, and such solvates are also intended to be encompassed withinthe scope of this invention. The skilled artisan will understand thatthe term compound as used herein, is meant to include solvated compoundsof Formula (I).

Where the processes for the preparation of the compounds according tocertain embodiments of the invention give rise to mixture ofstereoisomers, these isomers may be separated by conventional techniquessuch as preparative chromatography. The compounds may be prepared inracemic form, or individual enantiomers may be prepared either byenantiospecific synthesis or by resolution. The compounds may, forexample, be resolved into their component enantiomers by standardtechniques, such as the formation of diastereomeric pairs by saltformation with an optically active acid, such as(−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-1-tartaric acidfollowed by fractional crystallization and regeneration of the freebase. The compounds may also be resolved by formation of diastereomericesters or amides, followed by chromatographic separation and removal ofthe chiral auxiliary. Alternatively, the compounds may be resolved usinga chiral HPLC column.

One embodiment of the present invention is directed to a composition,including a pharmaceutical composition, comprising, consisting of,and/or consisting essentially of the (+)-enantiomer of a compound ofFormula (I) wherein said composition is substantially free from the(−)-isomer of said compound. In the present context, substantially freemeans less than about 25%, preferably less than about 10%, morepreferably less than about 5%, even more preferably less than about 2%and even more preferably less than about 1% of the (−)-isomer calculatedas.

${\% \mspace{11mu} ( + )\mspace{11mu} \text{-}{enantiomer}} = {\frac{\left( {{mass}\mspace{11mu} ( + )\mspace{11mu} \text{-}{enantiomer}} \right)}{\left( {{mass}\mspace{11mu} ( + )\mspace{11mu} \text{-}{enantiomer}} \right) + \left( {{mass}\mspace{11mu} ( - )\mspace{11mu} \text{-}{enantiomer}} \right)} \times 100.}$

Another embodiment of the present invention is a composition, includinga pharmaceutical composition, comprising, consisting of, and consistingessentially of the (−)-enantiomer of a compound of Formula (I) whereinsaid composition is substantially free from the (+)-isomer of saidcompound. In the present context, substantially free from means lessthan about 25%, preferably less than about 10%, more preferably lessthan about 5%, even more preferably less than about 2% and even morepreferably less than about 1% of the (+)-isomer calculated as

${\% \mspace{11mu} ( - )\mspace{11mu} \text{-}{enantiomer}} = {\frac{\left( {{mass}\mspace{11mu} ( - )\mspace{11mu} \text{-}{enantiomer}} \right)}{\left( {{mass}\mspace{11mu} ( + )\mspace{11mu} \text{-}{enantiomer}} \right) + \left( {{mass}\mspace{11mu} ( - )\mspace{11mu} \text{-}{enantiomer}} \right)} \times 100.}$

During any of the processes for preparation of the compounds of thevarious embodiments of the present invention, it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, Second Edition, J. F. W. McOmie, Plenum Press, 1973;T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis,John Wiley & Sons, 1991; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, Third Edition, John Wiley & Sons, 1999. Theprotecting groups may be removed at a convenient subsequent stage usingmethods known from the art.

Even though the compounds of embodiments of the present invention(including their pharmaceutically acceptable salts and pharmaceuticallyacceptable solvates) can be administered alone, they will generally beadministered in admixture with a pharmaceutically acceptable carrier, apharmaceutically acceptable excipient and/or a pharmaceuticallyacceptable diluent selected with regard to the intended route ofadministration and standard pharmaceutical or veterinary practice. Thus,particular embodiments of the present invention are directed topharmaceutical and veterinary compositions comprising compounds ofFormula (I) and at least one pharmaceutically acceptable carrier,pharmaceutically acceptable excipient, and/or pharmaceuticallyacceptable diluent.

By way of example, in the pharmaceutical compositions of embodiments ofthe present invention, the compounds of Formula (I) may be admixed withany suitable binder(s), lubricant(s), suspending agent(s), coatingagent(s), solubilizing agent(s), and combinations thereof.

Solid oral dosage forms, such as tablets or capsules, containing thecompounds of the present invention may be administered in at least onedosage form at a time, as appropriate. It is also possible to administerthe compounds in sustained release formulations.

Additional oral forms in which the present inventive compounds may beadministered include elixirs, solutions, syrups, and suspensions; eachoptionally containing flavoring agents and coloring agents.

Alternatively, compounds of Formula (I) can be administered byinhalation (intratracheal or intranasal) or in the form of a suppositoryor pessary, or they may be applied topically in the form of a lotion,solution, cream, ointment or dusting powder. For example, they can beincorporated into a cream comprising, consisting of, and/or consistingessentially of an aqueous emulsion of polyethylene glycols or liquidparaffin. They can also be incorporated, at a concentration of betweenabout 1% and about 10% by weight of the cream, into an ointmentcomprising, consisting of, and/or consisting essentially of a white waxor white soft paraffin base together with any stabilizers andpreservatives as may be required. An alternative means of administrationincludes transdermal administration by using a skin or transdermalpatch.

The pharmaceutical compositions of the present invention (as well as thecompounds of the present invention alone) can also be injectedparenterally, for example intracavernosally, intravenously,intramuscularly, subcutaneously, intradermally or intrathecally. In thiscase, the compositions will also include at least one of a suitablecarrier, a suitable excipient, and a suitable diluent.

For parenteral administration, the pharmaceutical compositions of thepresent invention are best used in the form of a sterile aqueoussolution that may contain other substances, for example, enough saltsand monosaccharides to make the solution isotonic with blood.

For buccal or sublingual administration, the pharmaceutical compositionsof the present invention may be administered in the form of tablets orlozenges, which can be formulated in a conventional manner.

By way of further example, pharmaceutical compositions containing atleast one of the compounds of Formula (I) as the active ingredient canbe prepared by mixing the compound(s) with a pharmaceutically acceptablecarrier, a pharmaceutically acceptable diluent, and/or apharmaceutically acceptable excipient according to conventionalpharmaceutical compounding techniques. The carrier, excipient, anddiluent may take a wide variety of forms depending upon the desiredroute of administration (e.g., oral, parenteral, etc.). Thus for liquidoral preparations, such as suspensions, syrups, elixirs and solutions,suitable carriers, excipients and diluents include water, glycols, oils,alcohols, flavoring agents, preservatives, stabilizers, coloring agentsand the like; for solid oral preparations, such as powders, capsules andtablets, suitable carriers, excipients and diluents include starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Solid oral preparations also may beoptionally coated with substances, such as, sugars, or beenterically-coated so as to modulate the major site of absorption anddisintegration. For parenteral administration, the carrier, excipientand diluent will usually include sterile water, and other ingredientsmay be added to increase solubility and preservation of the composition.Injectable suspensions or solutions may also be prepared utilizingaqueous carriers along with appropriate additives, such as solubilizersand preservatives.

A therapeutically effective amount of a compound of Formula (I) or apharmaceutical composition thereof includes a dose range from about 0.1mg to about 3000 mg, or any particular amount or range therein, inparticular from about 1 mg to about 1000 mg, or any particular amount orrange therein; or, more particularly, from about 10 mg to about 500 mg,or any particular amount or range therein, of active ingredient in aregimen of about 1 to about 4 times per day for an average (70 kg)human; although, it is apparent to one skilled in the art that thetherapeutically effective amount for a compound of Formula (I) will varyas will the diseases, syndromes, conditions, and disorders beingtreated.

For oral administration, a pharmaceutical composition is preferablyprovided in the form of tablets containing about 0.01, about 10, about50, about 100, about 150, about 200, about 250, and about 500 milligramsof a compound of Formula (I).

Advantageously, a compound of Formula (I) may be administered in asingle daily dose, or the total daily dosage may be administered individed doses of two, three and four times daily.

Optimal dosages of a compound of Formula (I) to be administered may bereadily determined and will vary with the particular compound used, themode of administration, the strength of the preparation and theadvancement of the disease, syndrome, condition or disorder. Inaddition, factors associated with the particular subject being treated,including subject gender, age, weight, diet and time of administration,will result in the need to adjust the dose to achieve an appropriatetherapeutic level and desired therapeutic effect. The above dosages arethus exemplary of the average case. There can be, of course, individualinstances wherein higher or lower dosage ranges are merited, and suchare within the scope of this invention.

Compounds of Formula (I) may be administered in any of the foregoingcompositions and dosage regimens or by means of those compositions anddosage regimens established in the art whenever use of a compound ofFormula (I) is required for a subject in need thereof.

As N-Type calcium channel blockers, the compounds of Formula (I) areuseful in methods for treating and/or preventing a disease, a syndrome,a condition or a disorder in a subject, including an animal, a mammaland a human in which the disease, the syndrome, the condition or thedisorder is affected by the modulation of the N-Type calcium channel.Such methods comprise, consist of and/or consist essentially ofadministering to a subject, including an animal, a mammal, and a humanin need of such treatment or prevention a therapeutically effectiveamount of a compound, salt or solvate of Formula (I). In particular, thecompounds of Formula (I) are useful for preventing or treating pain,such as inflammatory pain or neuropathic pain, or diseases, syndromes,conditions or disorders causing such pain.

General Synthetic Methods

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic methods described below andillustrated in the schemes and examples that follow. Since the schemesare an illustration, the invention should not be construed as beinglimited by the chemical reactions and conditions described in theschemes. The various starting materials used in the schemes and examplesare commercially available or may be prepared by methods well within theskill of persons versed in the art. The variables are as defined herein.

The following solvents, reagents or scientific terminology may bereferred to by their abbreviations:

-   TLC Thin Layer Chromatography-   DCM Dichloromethane-   DCE 1,2-Dichloroethane-   THF Tetrahydrofuran-   MeOH Methanol-   EtOH Ethanol-   IPA Isopropyl alcohol-   n-BuOH n-Butanol-   EtOAc Ethyl acetate-   Et₂O Diethyl ether-   DMA N,N-Dimethylacetamide-   DMF N,N-Dimethylformamide-   Et₃N Triethylamine-   DMSO Dimethylsulfoxide-   DIPEA Diisopropylethylamine (Hunig's base)-   HEK Human embryonic kidney-   MeI Methyliodide-   NBS N-Bromosuccinimide-   TFA Trifluoroacetic acid-   PTSA p-Toluenesulfonic acid-   AcOH Acetic acid-   Boc tert-butoxycarbonyl-   Cat Catalytic-   mL milliliters-   mol moles-   mmol millimoles-   h hour or hours-   min minute or minutes-   g grams-   mg milligrams-   μL Microliters-   eq Equivalents-   rt or RT Room temperature, ambient, about 27° C.-   MS Mass spectrometry-   NA Not available-   NE No Effect-   tmhd Dipivaloylmethanato

Scheme A illustrates a route for the synthesis of certain compounds ofthe present invention wherein R² is an optionally substituted phenyl oran optionally substituted heteroaryl as defined herein.

A compound of formula a1 is either commercially available or may beprepared by methods known in the scientific literature. A compound offormula a1 may be reacted with a compound of formula a2 in the presenceof an appropriate Lewis acid such as trimethylaluminum or the like, inan aprotic organic solvent such as toluene, at a temperature from about0° C. to about 70° C., to afford a compound of formula a3. A compound offormula a3 may be treated with a compound of formula a4 in the presenceof an appropriate inorganic base such as sodium bicarbonate, at about100° C., to afford a compound of formula (I)-A. A compound of formula(I)-A may be treated with NCS to afford compound of formula (I)-A1.

Alternatively, an appropriately substituted carboxylic acid compound offormula a6 (commercially available or prepared by methods known in thescientific literature) may be converted to its corresponding acidchloride by the action of an appropriate chlorinating agent such asoxalyl chloride, thionyl chloride, or the like, in an organic solventsuch as dichloromethane, at a temperature of about 0° C. to roomtemperature, to afford a compound of formula a7. A compound of formulaa7 may be converted to an amide of formula a8 via treatment with anappropriately substituted amine of formula a2, in the presence of anon-nucleophilic tertiary amine base such as triethylamine, in anorganic solvent such as dichloromethane, at a temperature of about 0° C.to room temperature. Conversion of a compound of formula a8 to acompound of formula a3 may be accomplished by treatment with achlorinating reagent such as phosphorus pentachloride, in an organicsolvent such as chloroform, at about room temperature, followed byreaction with ammonia gas at a temperature of about 0° C.

Scheme B illustrates a route for the synthesis of certain compounds ofthe present invention wherein R¹ is an optionally substituted phenyl asdefined herein.

A compound of formula b1 may be converted to its corresponding phenylcyanide in the presence of zinc cyanide, a transition metal catalyst,dimethylformamide, and suitable ligands, to afford compounds of Formula(1)-B wherein R¹ is a cyano-substituted phenyl ring.

Scheme C illustrates a route for the synthesis of certain compounds ofthe present invention wherein R¹ is an optionally substitutedphenylsulfonyl or alkylsulfonyl as defined herein.

A compound of formula a1 may be reacted with ammonium chloride, in thepresence of an appropriate Lewis acid such as trimethylaluminum or thelike, in an aprotic organic solvent such as toluene, at a temperaturefrom about 0° C. to about 70° C., to afford a compound of formula cl. Acompound of formula c1 may be reacted with a compound of formula a4 inthe presence of an appropriate inorganic base such as sodiumbicarbonate, at about 100° C., to afford a compound of formula c2. Acompound of formula c2 may be treated with an appropriately substitutedsulfonyl chloride in the presence of a non-nucleophilic tertiary aminebase such as triethylamine, in an organic solvent such asdichloromethane, at a temperature of about 0° C. to room temperature, toafford a compound of formula (1)-C.

Scheme D illustrates a route for the synthesis of certain compounds ofthe present invention wherein R^(1d) is an optionally substitutedphenylmethyl or heteroaryl-methyl group as defined by the scope of theinvention.

A compound of formula c2 may be reacted with an inorganic base such asNaH, K₂CO₃ or Cs₂CO₃, in the presence of an appropriatephenylmethyl-halide or heteroarylmethyl-halide to afford a compound offormula (I)-D.

Scheme E illustrates a route for the synthesis of certain compounds ofthe present invention wherein G is G2.

Commercially available ethoxy ethylene may be treated with a strongorganic base such as an alkyllithium base, organomagnesium bromide, orthe like, at 0° C., followed by addition of compound e1, to affordcompound e2. Compound e2 may be treated with a brominating reagent suchas hydrogen bromide in acetic acid, NBS, or the like, at 0° C. to roomtemperature, to afford compound e3. A compound of formula a3 may betreated with a compound of formula e3 in the presence of an appropriateinorganic base such as sodium bicarbonate, at about 100° C., to afford acompound of formula (I)-E.

Scheme F illustrates a route for the conversion of certain compounds ofFormula (I)-F1, wherein G is G2, to compounds of Formulae (I)-F2 and(I)-F3.

A compound of formula (I)-F1, prepared according to the methodsdescribed in Scheme E, may be converted to a compound of formula (I)-F2(wherein G is G3) in the presence of zinc cyanide, a transition metalcatalyst, dimethylformamide, and suitable ligands. Reaction of acompound of formula (I)-F2 may occur by the action of a hydride sourcesuch as triphenylsilane, or the like, in the presence of Mn(tmhd)3, at atemperature of about 0° C. to room temperature in an oxygen atmosphere,to afford a compound of formula (I)-F3.

SPECIFIC EXAMPLES

Yields reported herein refer to purified products (unless specified) andare not optimized. Analytical TLC was performed on Merck silica gel 60F254 aluminium-backed plates. Compounds were visualized by UV lightand/or stained either with iodine, potassium permanganate or ninhydrinsolution. Flash column chromatography was performed on silica gel(100-200 M) or flash chromatography. ¹H-NMR spectra were recorded on aBruker Avance-400 MHz spectrometer with a BBO (Broad Band Observe) andBBFO (Broad Band Fluorine Observe) probe. Chemical shifts (δ) areexpressed in parts per million (ppm) downfield by reference totetramethylsilane (TMS) as the internal standard. Splitting patterns aredesignated as s (singlet), d (doublet), t (triplet), q (quartet), m(multiplet) and br s (broad singlet). Coupling constants (J) are givenin hertz (Hz). LC-MS analyses were performed using the ElectrosprayIonization (ESI) technique.

A. Preparation of Chemical Intermediates Example 1 Preparation ofIntermediate A1; N-(4-cyanophenyl)-2-methoxybenzimidamide

To a stirred solution of 2-methoxybenzonitrile (10 g, 0.075 mol) intoluene (200 ml) at 0° C. was added trimethylaluminum (90 mL, 0.09 mol)drop-wise over a period of 10 min. The reaction mixture was then stirredat room temperature for 3 h followed by addition of 4-aminobenzonitrile(8.6 g, 0.074 mol) in toluene 100 mL. The reaction mixture was heated to70° C. for 16 h. After confirming the completion by LCMS the reactionmixture was quenched with ice-cold water; the aqueous layer was filteredthrough a pad of diatomaceous earth, and the resultant filtrate waswashed with ethyl acetate. The aqueous layer was extracted with ethylacetate (2×100 mL). The combined organic extracts were washed withbrine, dried over anhydrous Na₂SO₄, filtered, and concentrated underreduced pressure to provide a residue. Purification by columnchromatography on silica gel (100-200 mesh) using ethyl acetate inhexane afforded the title compound as a white solid. (12.8 g, 68%).

By using analogous protocols as described in the foregoing example theintermediates described in Table 1 have been prepared using appropriatestarting materials

TABLE 1 Intermediate No. Structure  A2

 A3

 A4

 A5

 A6

 A7

 A8

 A9

A10

A11

A12

A13

A14

A15

A16

A17

A18

A19

A20

A21

A22

A23

A24

A25

A26

A27

A28

A29

A30

A31

A32

A33

A34

A35

A36

A37

A38

A39

A40

A41

A42

A43

A44

A45

A46

A47

A48

A49

A50

A51

A52

A53

A54

A55

A56

A57

A58

A59

A60

A61

A62

Example 2 Preparation of Intermediate A-63 ;2-methoxy-N-(6-(trifluoromethyl)pyridin-3-yl)nicotinimidamide

Step 1. 2-Methoxy-nicotinoyl chloride: To a stirred solution of2-methoxynicotinic acid (2 g, 0.013 mol) in DCM (20 mL) under a N₂atmosphere was added oxalyl chloride (2 mL, 0.026 mol) drop-wise at 0°C. followed by the addition of a catalytic amount of DMF (2 drops). Thereaction mixture was stirred at room temperature for 2 h. Uponcompletion of the reaction, the solvent was removed under reducedpressure in an inert atmosphere to provide title compound as a thickliquid (2.1 g, 98%).

Step 2. 2-Methoxy-N-(6-trifluoromethyl-pyridin-3-yl)-nicotinamide To astirred solution of 6-(trifluoromethyl)pyridin-3-amine (1.8 g, 0.0011mol) in DCM (20 mL) under a N₂ atmosphere was added triethylamine (4.9mL, 0.035 mol) at 0° C. followed by the drop-wise addition of2-methoxy-nicotinoyl chloride (2 g, 0.0011 mol) in DCM (5 mL). Thereaction mixture was stirred at room temperature for 2 h. Uponcompletion of the reaction, the solvent was evaporated and resultantresidue was partitioned between DCM and water. The organic layer wasseparated and washed with brine, dried over anhydrous Na₂SO₄, filtered,and concentrated to afford the title compound as an off-white solid(2.02 g, 61.3%). LCMS: 298.1[M+H]⁺.

Step 3. 2-methoxy-N-(6-(trifluoromethyl)pyridin-3-yl)nicotinimidamide:To a stirred solution of PC15(0.17 g, 0.0084 mol) in chloroform (5 mL)at room temperature under a N₂ atmosphere was added2-methoxy-N-(6-trifluoromethyl-pyridin-3-yl)-nicotinamide (0.5 g,0.00168 mol). The reaction mixture was stirred at 61° C. for 30 min. Thereaction mixture was cooled to 0° C. followed by bubbling of ammonia gasfor 1 h. The reaction was quenched with NaHCO₃, partitioned between DCMand water. The organic layer was separated and washed with brine, driedover anhydrous Na₂SO₄, filtered, and concentrated to afford titlecompound as an off-white solid (0.25 g, 50.7%). LCMS- 297.1 [M+H]⁺. Byusing analogous protocols as described in the foregoing example thecompounds described in FIG. 1 have been prepared using appropriatestarting materials

Example 3 Preparation of intermediate A71;2-bromo-1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-yl)ethanone

Step 1. 2,2,6,6-tetramethyldihydro-2H-pyran-4(3H)-one: To a stirredsolution of 2,6-dimethylhepta-2,5-dien-4-one (100 g, 0.724 mol) wasadded 6N HCl (600 mL), then the reaction mixture was heated to 45° C.for 7 days. Upon completion, the reaction was quenched with ice coldwater and extracted with ethyl acetate (4×150 mL). The combined organicextracts were washed with brine, dried over anhydrous Na₂SO₄, filtered,and concentrated under reduced pressure to provide a residue.Purification by column chromatography on silica gel (100-200 mesh) usingethyl acetate in hexane afforded the title compound as a yellow liquid.(yield 28 g, 25%)

Step 2. 2,2,6,6-tetramethyltetrahydro-2H-pyran-4-carbonitrile: To astirred solution of 2,2,6,6-tetramethyldihydro-2H-pyran-4(3H)-one (30 g,0.192 mol) in dimethoxyethane (400 mL) was added tosylmethyl isocyanide(48.7 g, 0.249 eq) followed by the addition of tert-butyl alcohol (24.1g, 0.326) at room temperature. The reaction mixture was cooled to 0° C.followed by portion-wise addition of potassium tert-butoxide (53.8 g,0.48 mol). It was stirred at room temperature for 12 h. The reactionmixture was filtered after dilution with diethyl ether at 0° C. and theresidue was further washed with diethyl ether. The resultant filtratewas concentrated to provide the title compound as a yellow semi-solid(22 g, 68%)

Step 3. 2,2,6,6-tetramethyltetrahydro-2H-pyran-4-carboxylic acid: To astirred solution of2,2,6,6-tetramethyltetrahydro-2H-pyran-4-carbonitrile (22 g, 0.131 mol)in water (400 mL) was added KOH (45 g, 0.815 mol) and the reactionmixture was allowed to reflux for 8 h. The completion of the reactionwas confirmed by TLC. The reaction mixture was diluted with water andextracted with dichloromethane (3×100 mL). The aqueous layer wasacidified with 1N HCl, extracted with dichloromethane. The combinedorganic extracts were washed with brine, dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure to provide a residue.Purification by column chromatography on silica gel (100-200 mesh) usingethyl acetate in hexane afforded the title compound as a pale yellowsolid (13 g, 52%).

Step 4. 2,2,6,6-tetramethyltetrahydro-2H-pyran-4-carbonyl chloride: To astirred solution of 2,2,6,6-tetramethyltetrahydro-2H-pyran-4-carboxylicacid (2.7 g, 0.0144 mol) in DCM (30 mL) was added oxalyl chloride (3.6g, 0.0289 mol) at 0° C. The reaction mixture was allowed stirred for 3 hat room temperature and then concentrated to provide the title compoundas a black thick liquid (2.6 g, crude). It was used in the next stepwithout further purification.

Step 5. 2-diazo-1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)ethanone:To a stirred solution of2,2,6,6-tetramethyltetrahydro-2H-pyran-4-carbonyl chloride (2.6 g, 0.012mol) in dichloromethane (20 mL) was added trimethylsilyldiazomethane(2.9 g, 0.025 mol) at 0° C. after which it was stirred for 12 h at rt.The completion of the reaction was confirmed by TLC. The reactionmixture was concentrated under reduced pressure to provide a cruderesidue of the title compound as a black thick liquid which was used inthe next step without further purification. (2.5 g, crude)

Step 6. 2-bromo-1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-yl)ethanone:

To a stirred solution of2-diazo-1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)ethanone. (2.5 g,0.011 mol) in diethyl ether (20 mL) was added aqueous hydrobromic acid(8 mL) drop wise at 0° C. The stirring was continued for 3 h at 0° C.The completion of the reaction was confirmed by TLC. The reactionmixture was quenched with 10% NaHCO₃ aqueous solution (50 mL). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to provide a crude residue of thetitle compound as a yellow liquid which was used in the next stepwithout further purification. (2.4 g, crude).

Step 7. 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)ethanone: To astirred solution of2,2,6,6-tetramethyltetrahydro-2H-pyran-4-carbonitrile (2 g, 0.012 mol)in THF (25 mL) was added MeMgBr (3M in Et₂O) (4.7 mL, 0.0036 mol) at−78° C. and the reaction was slowly allowed to reach room temperatureand stirred for overnight. After completion of the reaction, thereaction was quenched with saturated NH₄Cl solution at 0° C. andextracted with EtOAc (2×75 mL). The combined organic extracts werewashed with brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure to provide a residue. Purificationby column chromatography on silica gel (100-200 mesh) using ethylacetate in hexane afforded the title compound as thick liquid. (1.54 g,70%).

Step 8. 2-bromo-1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)ethanone:

To a stirred solution of1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)ethanone (0.15 g, 0.0008mol) in EtOH (3 mL) was added Br₂ solution (0.06 mL, 0.0012 mol) at 0°C. and the reaction was stirred for overnight. After completion of thereaction, the reaction was diluted with ice water and extracted with DCM(2×50 mL). The combined organic extracts were washed with NaHCO₃, brine,dried over anhydrous Na₂SO₄, filtered, and concentrated under reducedpressure to provide the crude title compound which was used in thesubsequent stage without purification. Yield: 0.35 g (Crude).

Example 4 Preparation of IntermediateA72;2-bromo-1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)propan-1-one

Step 1. 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)propan-1-one: Toa stirred solution of2,2,6,6-tetramethyltetrahydro-2H-pyran-4-carbonitrile (0.5 g, 0.003 mol)in THF (5 mL) was added EtMgBr (3M in Et₂O) (1.19 mL, 0.0036 mol) at−78° C. and the reaction was slowly allowed to reach room temperatureand stirred for overnight. After completion of the reaction, thereaction was quenched with saturated NH₄Cl solution at 0° C. andextracted with EtOAc (2×10 mL). The combined organic extracts werewashed with brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure to provide a residue. Purificationby column chromatography on silica gel (100-200 mesh) using ethylacetate in hexane afforded the title compound as colorless solid. (0.25g, 42.3%)

Step 2.2-bromo-1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)propan-1-one: Toa stirred solution of1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)propan-1-one (0.2 g,0.001 mol) in EtOH (5 mL) was added Br₂ solution (0.078 mL, 0.0015 mol)at 0° C. and the reaction was stirred for overnight. After completion ofthe reaction, the reaction was diluted with ice water and extracted withDCM (2×50 mL). The combined organic extracts were washed with brine,dried over anhydrous Na₂SO₄, filtered, and concentrated under reducedpressure to provide the crude title compound which was used in thesubsequent stage without purification. Yield: 0.35 g (Crude).

Example 5 Preparation of Intermediate A74:2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole

Step 1. 2-methoxybenzimidamide: To a stirred solution of ammoniumchloride (6 g, 0.113 mol) in toluene (80 mL) at 0° C. was addedtrimethylaluminium (2.97 g, 0.041 mol) drop wise for a period of 10 min.The reaction mixture was stirred for 3 h at room temperature followed byaddition of 2-methoxybenzonitrile (5 g, 0.037 mol) in toluene (10 mL).The reaction was then heated to 70° C. for 16 h. After completion, thereaction was quenched with ice cold water, filtered through diatomaceousearth, and washed with ethyl acetate. The aqueous layer was extractedwith ethyl acetate (2×). The combined organic extracts were washed withbrine, dried over anhydrous Na₂SO₄, filtered, and concentrated underreduced pressure to provide a residue. Purification by columnchromatography on silica gel (100-200 mesh) using ethyl acetate inhexane afforded the title compound as a solid (4.5 g, 80%).

Step 2.2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole:To a stirred solution of 2-methoxybenzimidamide A73 (0.6 g, 0.004 mol)in 1,4- dioxane (20 mL) was added2-bromo-1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)ethanone A71(1.04 g, 0.004 mol), followed by the addition of NaHCO₃ (1 g, 0.012mol). The reaction mixture was refluxed for 5 h. The reaction wasquenched with ice cold water after completion. The aqueous layer wasextracted with ethyl acetate (3×25 mL). The combined organic extractswere washed with brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure to provide a residue. Purificationby column chromatography on silica gel (100-200 mesh) using ethylacetate in hexane afforded the title compound as a white solid (0.5 gcrude).

Example 6 Preparation of Intermediate A75:2-bromo-1-(4-hydroxy-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)ethanone

Step 1.1-(4-hydroxy-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)ethanone: To astirred solution of ethoxyethene (1.84 g, 25.5 mmol) in THF (40 mL) wasadded ^(t)BuLi (16 mL, 25.6 mmol) at −78° C. The reaction mixture wasslowly allowed to warm to 10° C. followed by addition of2,2,6,6-tetramethyldihydro-2H-pyran-4(3H)-one (2 g, 12.8 mmol). Themixture was stirred for 16 h at room temperature. The reaction wasquenched by the addition of HCl (3 mL) in aqueous methanol (20 mL, MeOH: H₂O=1:1). The combined organic extracts were washed with brine, driedover anhydrous Na₂SO₄, filtered, and concentrated under reduced pressureto provide the crude title compound as an off-white solid (1.2 g) whichwas used in the next step without further purification.

Step 2. (See below)

Step 3.2,2,6,6-Tetramethyl-4-trimethylsilanylethynyl-tetrahydro-pyran-4-ol. Toa solution of ethynyl-trimethyl-silane (5.5 mL, 38.4 mmol) in dry THF(25 mL) was added n-BuLi (32 mL, 38.4 mmol) at −78° C. and the mixturewas stirred at that temperature for 45 min followed by addition of2,2,6,6-tetramethyl-tetrahydro-pyran-4-one (5.0 g, 32 mmol) in dry THF(25 mL) at −78° C. The mixture was stirred for 1 h and then quenchedwith saturated NH₄Cl solution and extracted with ethyl acetate (3×100mL). The combined organic extract was washed with water and brinesolution, dried over Na₂SO₄, filtered, and concentrated under reducedpressure to afford the product as sticky white solid. Crude product wasforwarded for next stage without purification. Yield: 8.0 g, crude.

Step 4. 4-Ethynyl-2,2,6,6-tetramethyl-tetrahydro-pyran-4-ol. To astirred solution of2,2,6,6-tetramethyl-4-trimethylsilanylethynyl-tetrahydro-pyran-4-ol (8.0g, 0.031 mol) in MeOH (120 mL) was added potassium carbonate (10.86 g,0.078 mol) and the mixture was stirred at rt for 12 h. MeOH wasevaporated to obtain a residue, to which water was added. The mixturewas extracted with ethyl acetate (3×100 mL). The organic portion waswashed with brine solution, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to afford the crude product, whichwas triturated with n-pentane to afford the purified product as anoff-white solid. (Yield: 3.5 g, 61%).

Step 5.1-(4-hydroxy-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)ethanone. To astirred solution of HgO (0.185 g, 0.085 mmol) in acetone/H₂O (30 mL/ 4mL) was added H₂SO₄ (0.03 mL) and the mixture was heated to 60° C.,followed by addition of4-ethynyl-2,2,6,6-tetramethyl-tetrahydro-pyran-4-ol (3) (2.6 g, 1.42mmol) in acetone (10 mL) drop wise at that temperature. Afterconsumption of starting material (TLC), the reaction mixture wasconcentrated , diluted with cold water (50 mL) and extracted with EtOAc(3×50 mL). The combined organic extracts were washed with water andbrine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure to afford the crude product. Yield: 2.5 g (87%).

Step 2.2-bromo-1-(4-hydroxy-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)ethanone.

To a stirred solution of1-(4-hydroxy-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)ethanone (1.1g, 0.0054 mol) in CHCl₃ (30 mL) was added two drops of HBr/AcOH at 0°C., followed by addition of Br₂ (0.3 mL, 0.006 mol) in CHCl₃ (2 mL). Thetemperature was gradually increased to room temperature and the reactionmixture was stirred for 4 h. After completion of the reaction, thereaction mixture was diluted with DCM (100 mL). The DCM solution waswashed with NaHCO₃, brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure to provide the crude title compoundas a thick liquid which is used directly for the next stage withoutfurther purification. Yield: 1.2 g (Crude).

B. Preparation of Final Compounds Example 7 Compound 1:4-(2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl)benzonitrile

To a stirred solution of N-(4-cyanophenyl)-2-methoxybenzimidamide A1(2.5 g, 0.0099 mol) and2-bromo-1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)ethanone A71(3.24 g, 0.0123 mol) in dioxane (50 mL) was added NaHCO₃ (1.67 g, 0.0199mol) and the reaction mixture was refluxed at 100° C. for 5 h. Aftercompletion of the reaction the mixture was concentrated under reducedpressure and quenched with ice cold water. The aqueous layer wasextracted with ethyl acetate (2×150 mL). The combined organic extractswere washed with brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure to provide a residue. The residuewas purified by column chromatography on silica gel (100-200 mesh) usingethyl acetate in hexane to afford the title compound 1 as a white solid.¹H NMR (400 MHz, CDCl₃) δ 7.61-7.57 (m, 3H), 7.38-7.34 (m,1H), 7.21 (d,J=8.4Hz, 2H), 7.05 (t, J=6.8Hz, 1H), 6.96 (s, 1H), 6.71 (d, J=8.4Hz,1H), 3.27 (s, 3H), 3.24 - 3.22 (m, 1H), 2.06-2.02 (m, 2H), 1.50-1.44 (m,2H), 1.36 (s, 6H), 1.25 (s, 6H); LCMS: 416.3 (M+H)⁺.

Using analogous protocols to those described in Example 7, the compoundsdescribed in Table 2 have been prepared using an appropriatelysubstituted amidine intermediate.

TABLE 2 Cpd No. Structure Compound Name Analytical data  2

4-(1-(4-fluorophenyl)-4- (2,2,6,6 tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-3-methoxypyridine ¹H NMR (400 MHz,DMSO-d₆) 8.29-8.26 (m, 2H), 7.50 (d, J = 4.4 Hz, 1H), 7.33 (s, 1H),7.28-7.16 (m, 4H), 3.32 (s, 3H), 3.15-3.08 (m, 1H), 1.90 (d, J = 2.8 Hz,2H), 1.40-1.39 (m, , 2H), 1.28 (s, 6H), 1.15 (s, 6 H). LCMS: 410.4 [M +H]⁺  3

4-(1-(4-ethoxyphenyl)-4- (2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-3-methoxypyridine ¹H NMR (400 MHz,DMSO-d₆) δ = 8.28- 8.29 (m, 2H), 7.94- 7.93 (m, 1H), 7.53- 7.45 (m, 2H),7.33 (s, 1H), 6.80 (d, J = 8.8 Hz, 1H), 4.29- 4.24 (q, 2H), 3.41 (s,3H), 3.14-3.08 (m, 1H), 1.93-1.89 (m, 2H), 1.36-1.24 (m, 3H), 1.21-1.12(m, 6H), 1.11-1.09 (m, 2H). LCMS: 436.2 [M + H]⁺  4

1-(4-fluorophenyl)-2-(2- methoxyphenyl)-4- (2,2,6,6-tetramethyltetrahydro-2H- pyran-4-yl)-1H-imidazole ¹H NMR (400 MHz,DMSO-d₆) δ = 7.45 (d, J = 6.8 Hz, 1H), 7.36 (t, J = 6.8 Hz, 1H),7.13-7.12 (m, 5H), 7.01 (J = 7.6 Hz, 1H), 6.87 (d, J = 8 Hz, 1H), 3.23(s, 3H), 3.10 (d J = 11.6 Hz, 1H), 1.91 (d, J = 11.6 Hz, 2H), 1.36 (t, J= 12.8 Hz, 2H), 1.28(s, 6H), 1.15 (s, 6H). LCMS: 409.2 [M + H]⁺  5

5-(2-(2-methoxyphenyl)- 4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 1-yl)-2-methylpyridine ¹H NMR (400 MHz,DMSO-d₆) δ = 8.18 (s, 1 H), 7.35-7.5 (m, 3 H), 7.28 (s, 1 H), 7.22 (d, J= 8.4 Hz, 1 H), 7.02 (t, J = 7.6 Hz, 1 H), 6.88 (d, J = 8.0 Hz 1 H),3.23 (s, 3 H), 3.03- 3.14 (m, 1 H), 2.43 (s, 3 H), 1.93 (t, J = 2.4 Hz,2 H), 1.36 (t, J = 12.8 Hz, 2 H), 1.28 (s, 6 H), 1.15 (s, 6 H). LCMS:406.5 [M + H]⁺.  6

2-(2-(2-methoxyphenyl)- 4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 1-yl)-5-methylpyridine ¹H NMR (400 MHz,DMSO-d₆) δ = 8.20 (s, 1H), 7.60 (d, J = 8 Hz, 1H), 7.50 (d, J = 1.2 Hz,1H), 7.35-7.39 (m, 2H), 7.03 (t, J = 7.6 Hz, 1H), 6.87-6.93 (m, 2H),3.16 (s, 3H), 3.07-3.13 (m, 1H), 2.26 (s, 3H), 1.93 (d, J = 2.8 Hz, 2H),1.39- 1.33 (m, 2H), 1.29 (s, 6H), 1.15 (s, 6H). LCMS: 406.3 [M + H]⁺  7

2-(2-methoxyphenyl)-1- (4-methoxyphenyl)-4- (2,2,6,6-tetramethyltetrahydro-2H- pyran-4-yl)-1H-imidazole ¹H NMR (400 MHz,DMSO-d₆) δ 7.40 (d, J = 7.6 Hz, 1H), 7.31 (t, J = 8 Hz, lH), 7.12 (s,1H), 6.99 (q, J = 8.8 Hz, J = 8.8 Hz, 1H), 6.87 (d, J = 8 Hz, 1H), 3.71(s, 3H), 3.26 (s, 3H), 3.08 (t, J = 12.4 Hz, 1H), 1.90 (dd, J = 2.8 Hz,J = 12.8 Hz, 2H), 1.36 (t, J = 12.8 Hz, 2H), 1.28 (s, 6H), 1.15 (s, 6H).LCMS: 421.2 [M + H]⁺  8

5-(2-(2-methoxyphenyl)- 4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 1-yl)-2-methylpyrimidine ¹H NMR (400 MHz,DMSO-d₆) δ 8.47 (s, 2 H), 7.51 (d, J = 1.6 Hz, 1 H), 7.43 (d, J = 1.2Hz, 1 H), 7.39 (s, 1 H), 7.08- 7.04 (m, 1 H), 6.90 (d, J = 8.4 Hz 1 H),3.27 (s, 3 H), 3.14-3.03 (m, 1 H), 2.60 (s, 3H), 1.94 (d, J = 2.8 Hz,2H), 1.42-1.36 (m, 2 H), 1.28 (s, 6 H), 1.15 (s, 6 H) LCMS: 407.5 [M +H]⁺  9

3-(1-(3-chlorobenzyl)-4- (2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-2-methoxypyridine ¹H NMR (400 MHz,DMSO-d₆) δ = 8.25 (d, J = 4 Hz, 1H), 7.67 (d, J = 8 Hz, 1H), 7.30 (t, J= 5.2 Hz, 2H), 7.05 (t, J = 11.2 Hz, 3H), 6.90 (s, 1H), 4.99 (s, 2H),3.78 (s, 3H), 3.08-3.01 (m, 1H), 1.86 (q, J = 2.8 & 2.9 Hz, 2H),1.32-1.40 (m, 2H), 1.26 (s, 6H), 1.12 (s, 6H). LCMS: 440.2 [M + H]⁺  10

3-(1-(4-fluorophenyl)-4- (2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-2-methoxypyridine ¹H NMR (400 MHz,DMSO-d₆) δ = 8.17 (d, J = 4.8 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.27(s, 1H), 7.1-7.26 (m, 4H), 7.07 (d, J = 5.2 Hz, 1H), 3.1 (s, 1H), 1.89(t, J = 15.6 Hz, 2H), 1.36 (t, J = 12.8 Hz, 2H), 1.28 (s, 6H), 1.14 (s,6H). LCMS: 410.5 [M + H]⁺  11

3-(1-(4-chlorophenyl)-4- (2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-2-methoxypyridine ¹H NMR: (400 MHz,CDCl₃) δ 8.16 (d, J = 3.2 Hz, 1H), 7.88 (d, J = 6.4 Hz, 1H), 7.30-7.27(m, 2H), 7.04 (d, J = 8.4 Hz, 2H), 6.97-6.93 (m, 2H), 3.48 (s, 3H),3.25-3.19 (m, 1H), 2.03 (d, J = 10.8 Hz, 2H), 1.51-1.44 (m, 2H), 1.36(s, 6H), 1.25 (s, 2H). LCMS 426.2 (M + H)⁺  12

4-(2-(3-methoxypyridin-2- yl)-4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 1-yl)benzonitrile ¹H NMR (400 MHz, DMSO-d₆) δ =8.19 (s, 1H), 7.75-7.85 (m, 2H), 7.40-7.50 (m, 3H), 7.26 (d, J = 8 Hz,2H), 3.45 (s, 3H), 3.05-3.20 (m, 1H), 1.92 (d, J = 11.6 Hz, 2H),1.30-1.40 (m, 2H), 1.29 (s, 6H), 1.16 (s, 6H). LCMS: 417.5 [M + H]⁺  13

4-(1-(4-chloro-3- fluorophenyl)-4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-3-methoxypyridine ¹H NMR (CDCl₃, 400 MHz)δ 8.35 (d, J = 4.8 Hz, 1H), 8.18 (s, 1H), 7.53 (d, J = 4.8 Hz, 1H),7.36-7.32 (m, 1H), 6.99- 6.96 (m, 2H), 6.82 (d, J = 8.4 Hz, 1H), 3.47(s, 3H), 3.25-3.19 (m, 1H), 2.02-1.99 (m, 2H), 1.50- 1.43(m, 2H), 1.35(s, 6H), 1.28 (s, 6H). LCMS: 444.4 [M + H]⁺  14

2-chloro-5-(2-(2- methoxyphenyl)-4- (2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 1-yl)benzonitrile ¹H NMR (CDCl₃, 400 MHz) δ7.57-7.55 (m, 1H), 7.47-7.46 (m, 1H), 7.42-7.35 (m, 1H), 7.26 (s, 1H),7.06-7.03 (m, 1H), 6.92 (s, 1H), 6.74 (d, J = 8.4 Hz, 1H), 3.37 (s, 3H),3.26-3.19 (m, 1H), 2.04-2.01 (m, 2H), 1.50-1.43 (m, 2H), 1.35 (s, 6H),1.29 (s, 6H). LCMS: 450.5 [M + H]⁺  15

4-(2-(2-methoxypyridin-3- yl)-4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 1-yl)-2-methylbenzonitrile ¹H NMR (CDCl₃, 400MHz) δ 8.20-8.18 (m, 1H), 7.94-7.91 (m, 1H), 7.55-7.53 (m, 1H), 7.11 (s,1H), 7.01-6.97 (m, 3H), 3.44 (s, 3H), 3.26- 3.19 (m, 1H), 2.50 (s, 3H),2.04-2.00 (m, 2H), 1.50-1.42 (m, 2H), 1.35 (s, 6H), 1.26 (s, 6H). LCMS:431.5 [M + H]⁺  16

2-methoxy-3-(4-(2,2,6,6- tetramethyltetrahydro-2H- pyran-4-yl)-1-(2,3,4-trifluorophenyl)-1H- imidazol-2-yl)pyridine ¹H NMR (400 MHz, DMSO):8.20-8.18 (m, 1H), 7.94-7.91 (m, 1H), 7.29-7.35 (m, 2H), 7.10- 7.07 (m,2H), 3.45 (s, 3H), 3.16-3.10 (m, 1H), 1.93-1.89 (m, 2H), 1.39- 1.33 (m,2H), 1.29 (s, 6H), 1.15 (s, 6H). LCMS: 446.4 [M + H]⁺  17

2-(1-(3-chloro-4- fluorophenyl)-4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-3-methoxypyridine ¹H NMR (400 MHz,DMSO-d₆) 8.18-8.17 (m, 1H), 7.47-7.35 (m, 5H), 7.02-7.00 (m, 1H), 3.51(s, 3H), 3.13-3.07 (m, 1H), 1.92 (d, J = 11.6 Hz, 2H), 1.37 (d, J = 13.2Hz, 2H), 1.29 (s, 6H), 1.15 (s, 6H). LCMS: 444.4 [M + H]⁺  18

4-(1-(3-chloro-4- fluorophenyl)-4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-3-methoxypyridine ¹H NMR (400 MHz,DMSO-d₆) 8.31-8.28 (m, 2H), 7.55-7.51 (m, 2H), 7.44-7.39 (m, 2H), 7.12-7.08 (m, 1H), 3.37 (s, 3H), 3.14-3.07 (m, 1H), 1.93-1.89 (m, 2H), 1.39-1.32 (m, 2H), 1.28 (s, 6H), 1.15 (s, 6H). LCMS: 444.4 [M + H]⁺  19

2-(1-(4-chloro-3- fluorophenyl)-4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-3-methoxypyridine ¹H NMR (400 MHz,DMSO-d₆) 8.19-8.17 (s, 1H), 7.55-7.51 (m, 1H), 7.48-7.42 (m, 2H), 7.37(s, 1H), 7.29-7.26 (m, 1H), 6.87-6.85 (m, 1H), 3.51 (s, 3H), 3.14-3.07(m, 1H), 1.93-1.89 (m, 2H), 1.39-1.33 (m, 2H), 1.29 (s, 6H), 1.15 (s,6H). LCMS: 444.4 [M + H]⁺  20

3-(1-(3-chloro-4- fluorophenyl)-4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-4-methoxypyridine ¹H NMR (400 MHz,DMSO-d₆) 8.51 (s, 1H), 8.48-8.47 (m, 1H), 7.54- 7.52 (m, 1H), 7.43-7.38(m, 2H), 7.15-7.11 (m, 1H), 6.98-6.97 (m, 1H) 3.40 (s, 3H), 3.05-3.15(m, 1H), 1.94-1.90 (m, 2H), 1.39-1.32 (m, 2H), 1.29 (s, 6H), 1.15 (s,6H). LCMS: 444.4 [M + H]⁺  21

4-(2-(2-methoxyphenyl)- 4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 1-yl)-2-methylbenzonitrile ¹H NMR (400 MHz,DMSO-d₆) 7.70 (d, J = 8 Hz, 1H), 7.49 (d, 7 = 7.6 Hz, 1H), 7.41 (t, 1H),7.34-7.33 (m, 2H), 7.05 (t, 1H), 6.98-6.96 (m, 1H), 6.89 (d, J = 8 Hz,1H), 3.18 (s, 3H), 3.13- 3.06 (m, 1H), 2.42 (s, 3H), 1.94-1.90 (m, 2H),1.39-1.32 (m, 2H), 1.29 (s, 6H), 1.15 (s, 6H). LCMS: 430.5 [M + H]⁺  22

5-(2-(2-methoxyphenyl)- 4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 1-yl)-2-methylbenzonitrile ¹H NMR (400 MHz,DMSO-d₆) 7.58 (s, 1H), 7.47 (d, J = 6.8 Hz, 1H), 7.38 (d, J = 7.6 Hz,2H), 7.31 (s, 1H), 7.25 (d, J = 7.2 Hz, 1H), 7.04 (t, 1H), 6.89 (d, J =8.4 Hz, 1H), 3.22 (s, 3H), 3.12- 2.98 (m, 1H), 2.44 (s, 3H), 1.92 (d, J= 12.8 Hz, 2H), 1.44-1.35 (m, 2H), 1.29 (s, 6H), 1.15 (s, 6H), LCMS:430.3 [M + H]⁺  23

3-(1-(3-fluoro-4- methoxyphenyl)-4- (2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-4-methoxypyridine ¹H NMR (400 MHz,DMSO-d₆) 8.20-8.18 (m, 1H), 7.89-7.87 (m, 1H), 7.25 (s, 1H), 7.16-7.06(m, 3H), 6.85 (d, J = 7.6 Hz, 1H), 3.81 (s, 3H), 3.41 (s, 3H), 3.12-3.05(m, 1H), 1.93-1.89 (m, 2H), 1.39-1.32 (m, 2H), 1.28 (s, 6H), 1.15 (s,6H). LCMS: 440.5 [M + H]⁺  24

3-(1-(4-fluoro-3- methoxyphenyl)-4- (2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-4-methoxypyridine ¹H NMR (400 MHz,DMSO-d₆) 8.20-8.18 (m, 1H), 7.91-7.88 (m, 1H), 7.32 (s, 1H), 7.20-7.15(m, 1H), 7.10-7.07 (m, 1H), 7.00-6.98 (m, 1H), 6.63-6.60 (m, 1H), 3.70(s, 3H), 3.39 (s, 3H), 3.13-3.07 (m, 1H) 1.94- 1.90 (m, 2H), 1.40-1.34(m, 2H), 1.29 (s, 6H), 1.15 (s, 6H). LCMS: 440.5 [M + H]⁺  25

5-(2-(2-methoxypyridin-3- yl)-4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 1-yl)-2-methylbenzonitrile ¹H NMR (400 MHz,DMSO-d₆) 8.20 (d, J = 2.4 Hz, 1H), 7.92 (d, J = 3.6 Hz, 1H), 7.66 (s,1H), 7.42 (d, J = 8.4 Hz, 1H), 7.37 (s, 1H), 7.29 (d, J = 2 Hz, 1H),7.11 (d, J = 4.8 Hz, 1H), 3.32 (s, 3H), 3.13-3.07 (m, 1H), 2.46 (s, 3H),1.92 (d, J = 13.2 Hz, 2H), 1.37 (d, J = 12.8 Hz, 2H), 1.29 (s, 6H), 1.15(s, 6H). LCMS: 431.5 [M + H]⁺  26

3-(1-(4-chlorophenyl)-4- (2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-4-methyl-4H-1,2,4- triazole ¹H NMR: ¹HNMR(400 MHz, DMSO-d₆) δ 8.41 (bs, 1H), 7.46 (d, J = 6.8 Hz, 2H), 7.29(t, J = 14 Hz, 3H), 3.83 (s, 3H), 1.88 (d, J = 11.6 Hz, 2H), 1.38 (d, J= 12.4 Hz, 2H), 1.28 (s, 6H), 1.15 (s, 6H). LCMS 400.46 [M + H]⁺  27

3-(1-(2-chlorobenzyl)-4- (2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-2-methoxypyridine ¹H NMR (CDCl₃, 400 MHz)δ 8.27 (s, 1 H), 7.7-7.84 (m, 1 H), 7.35 (d J = 7.2 Hz, 1 H), 7.18- 7.28(m, 2 H), 7.08 (s, 1 H), 6.9-7.0 (m, 1 H), 6.68 (s, 1 H), 5.13 (s, 1 H),5.05 (s, 1 H), 3.79 (s, 3 H), 2.68-2.80 (m, 1 H), 2.0-2.10 (m, 1 H),1.75- 1.86 (m, 1 H), 1.4-1.5 (m, 3 H), 1.16 (s, 6 H), 1.03 (s, 3 H),0.89 (s, 3 H). LCMS: 440.4 [M + H]⁺  28

3-(1-(4-chlorobenzyl)-4- (2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-2-methoxypyridine ¹H NMR (400 MHz,DMSO-d₆) δ 8.25 (d, J = 3.2 Hz, 1 H), 7.6-7.7 (m, 1 H), 7.33 (d, J = 8.4Hz, 2 H), 7.06-7.03 (m, 1 H), 6.98 (d, J = 6.8 Hz, 3 H), 4.97 (s, 2 H),3.78 (s, 3 H), 3.05-299 (m, 1 H), 1.86-1.82 (m, 2 H), 1.35- 1.30 (m, 1H), 1.25 (s, 7 H), 1.12 (s, 6 H). LCMS: 440.2 [M + H]⁺  29

4-(2-(2-methoxypyridin-3- yl)-4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 1-yl)-2-(trifluoromethyl) benzonitrile ¹H NMR(CDCl₃, 400 MHz) δ 8.2-8.3 (m, 1 H), 7.99-7.97 (m, 1 H), 7.78 (d, J = 8Hz, 1 H), 7.62 (s, 1 H), 7.3-7.4 (m, 1 H), 7.05-7.01 (m, 2 H), 3.4 (s, 3H), 3.26-3.20 (m, 1 H), 2.04-2.00 (m, 2 H), 1.51-1.45 (m, 2 H), 1.35 (s,6 H), 1.26 (s, 6 H). LCMS: 485.5 [M + H]⁺  30

3-(1-(2,4-difluorophenyl)- 4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-2-methoxypyridine ¹H NMR (400 MHz,DMSO-d₆) δ 8.21 (s, 1 H), 7.92 (d, J = 7.2 Hz, 1 H), 7.46-7.1 (m, 1 H),7.3-7.44 (m, 2 H), 7.09 (m, 2 H), 3.6 (s, 3 H), 3.1-3.2 (m, 1 H), 1.92(d, J = 12.8 Hz, 2 H), 1.38 (d, J = 13.2 Hz, 2H), 1.29 (s, 6H), 1.15 (s,6 H). LCMS: 428.5 [M + H]⁺  31

3-(1-(2,3-difluorophenyl)- 4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-2-methoxypyridine ¹H NMR (400 MHz,DMSO-d₆) δ 8.28 (t, J = 3.6 Hz, 1 H), 8.01 (t, J = 5.6 Hz, 1 H), 7.68(s, 1 H), 7.55-7.63 (m, 1 H), 7.22-7.27 (m, 1 H), 7.11- 7.19 (m, 2 H),3.48 (s, 3 H), 3.29-3.23 (m, 1 H), 1.98-1.93 (m, 2 H), 1.44- 1.38 (m,2H), 1.30 (s, 6 H), 1.17 (s, 6 H). LCMS: 428.5 [M + H]⁺  32

3-(2-(2-methoxyphenyl)- 4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 1-yl)benzonitrile ¹H NMR (400 MHz, DMSO-d₆) δ7.75 (d, J = 7.2 Hz, 1H), 7.67 (s, 1H), 7.53-7.50 (m, 2H), 7.42-7.37 (m,3H), 7.05 (t, J = 7.6 Hz, 1H), 6.68 (d, J = 8 Hz, 1H), 3.18 (s, 3H),3.10 (m, 1H), 1.93(d, J = 14.4 Hz, 2 H), 1.38(d, J = 12.8 Hz, 2H),1.32(s, 6H), 1.15 s, 6H). LCMS: 416.5 [M + H]⁺  33

4-(1-(3,4-difluorophenyl)- 4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-3-methoxypyridine ¹H NMR (CDCl₃, 400 MHz)δ 8.35 (d, J = 4.8 Hz, 1H), 8.1 (s, 1H), 7.52 (d, J = 4.8 Hz, 1H), 7.15-7.10 (m, 1H), 7.03-6.99 (m, 1H), 6.95 (s, 1H), 6.84 (d, J = 9.6 1H),3.49 (s, 3H), 3.25-3.19(m, 1H), 2.03 (d, J = 10 Hz, 2H), 1.50-1.43(m,2H), 1.36 (s, 6H), 1.26 (s, 6H). LCMS: 428.2 [M + H]⁺  34

2-methoxy-4-(2-(2- methoxyphenyl)-4- (2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 1-yl)benzonitrile ¹H NMR (CDCl₃, 400 MHz) δ7.60-7.59(d, J = 1.2 Hz, 1H), 7.52-7.50 (d, J = 8.4 Hz, 1H), 7.39- 7.35(m, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.98 ( s, 1H), 6.85 (d, J = 2.0 Hz,1H), 6.75 (d, J = 10.4 Hz, 1H), 6.60(s, 1H), 3.60 (s, 3H), 3.26 (s, 3H),3.26- 3.20 (m, 1H), 2.06-2.02 (m, 2H), 1.51-1.45 (m, 2H), 1.36 (s, 6H),1.26 (s, 6H). LCMS: 446.5 [M + H]⁺  35

2-(1-(3,4-difluorophenyl)- 4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-3-methoxypyridine ¹H NMR (400 MHz,DMSO-d₆) δ = 8.18-8.16 (m, 1H), 7.49-7.38 (m, 3H), 7.37-7.28 (m, 2H),6.87-6.85 (m, 1H), 3.51 (s, 3H), 3.14-3.17 (m, 1H), 1.92 (dd, J = 2.8Hz, J = 12.8 Hz, 2H), 1.39- 1.33 (m, 2H), 1.29 (s, 6H), 1.15 (s, 6H).LCMS: 428.23 [M + H]⁺  36

3-fluoro-4- (2-(2-methoxyphenyl)- 4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 1-yl)benzonitrile ¹H NMR (400 MHz, DMSO-d₆) δ =8.07 (d, J = 10.4 Hz, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.51 (d, J = 7.2Hz, 1H), 7.39-7.35 (m, 1H), 7.34-7.27 (m, 2H), 7.06-7.00 (m, 1H), 6.86(d, J = 8.4 Hz, 1H), 3.22 (s, 3H), 3.16-3.12 (m, 1H), 1.94-1.88 (m, 2H),1.41-1.33 (m, 2H), 1.29 (s, 6H), 1.15 (s, 6H). LCMS: 434.48 [M + H]⁺  37

2-methoxy-5-(2-(2- methoxyphenyl)-4- (2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 1-yl)benzonitrile ¹H NMR (400 MHz, DMSO-d₆) δ =7.57 (d, J = 2.4 Hz, 1H), 7.46 (dd, J = 2 Hz, J = 7.6 Hz, 1H), 7.41-7.36(m, 1H), 7.34- 7.31 (m, 1H), 7.26 (s, 1H), 7.18-7.16 (m, 1H), 7.04-6.98(m, 1H), 6.90- 6.88 (m, 1H), 3.88 (s, 3H), 3.28 (s, 3H), 3.11- 3.05 (m,1H), 1.91 (dd, J = 2.8 Hz, J = 12.8 Hz, 2H), 1.38-1.32 (m, 2H), 1.28 (s,6H), 1.15 (s, 6H). LCMS: 446.30 [M + H]⁺  38

1-(4-chlorophenyl)-2-(2- methoxyphenyl)-4- (2,2,6,6-tetramethyltetrahydro-2H- pyran-4-yl)-1H-imidazole ¹H NMR (CDCl₃, 400MHz) δ 7.55 (d, J = 6.4 Hz, 1H), 7.32 (t, J = 7.2 Hz, 1H), 7.55-7.23 (m,2H), 7.05-6.98 (m, 3H), 6.91 (s, 1H), 6.71 (d, J = 8.4 Hz, 1H), 3.23 (s,3H), 3.26-3.20 (m, 1H), 2.06-2.03 (m, 2H), 1.51-1.44 (m, 2H), 1.35 (s,6H), 1.25 (s, 6H). LCMS: 425.3 [M + H]⁺  39

5-chloro-2-(2-(2- methoxyphenyl)-4- (2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 1-yl)pyridine ¹H NMR (CDCl₃, 400 MHz) δ 8.41(d, J = 2.4 Hz, 1H), 7.63-7.60 (m, 1H), 7.50- 7.47 (m, 1H), 7.39-7.33(m, 2H), 7.05(t, 7.6 Hz, 1H), 6.81-6.75 (m, 2H), 3.35 (s, 3H),3.25-3.19 (m, 1H), 2.06- 2.07 (m, 2H), 1.49- 1.46 (m, 2H), 1.35 (s, 6H),1.25 (s, 6H). LCMS: 426.2 [M + H]⁺  40

3-(1-(3,4-difluorophenyl)- 4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-2-methoxypyridine ¹H NMR (400 MHz,DMSO-d₆) δ 8.19(dd J = 6.4 Hz, 1.6 Hz, 1H), 7.90(dd, J = 8.8 Hz, 1.6 Hz1H), 7.45-7.36 (m, 2H), 7.3l(s, 1H), 7.10- 7.07(m, 1H), 6.93(d, 8 Hz,1H), 3.388(s, 3H), 3.086 (m, 1H), 1.92- 1.881(m, 2H), 1.38-1.318 (m,2H), 1.139(s, 6H), 1.127(s, 6H); LCMS: 428.3 [M + H]⁺  41

1-(4-chloro-3- fluorophenyl)-2-(2- methoxyphenyl)-4- (2,2,6,6-tetramethyltetrahydro-2H- pyran-4-yl)-1H-imidazole ¹H NMR (CDCl₃, 400MHz) δ 7.56-7.53 (dd, J = 7.2 Hz, 1.2 Hz, 1H), 7.37-7.31 (m, 1H), 7.27(t, J = 8 Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 6.97- 6.94 (dd, J = 9.6 Hz,2.4 Hz, 1H), 6.91 (s, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 8.4Hz, 1H), 3.37 (s, 3H), 3.23-3.22 (m, 1H), 2.06-2.02 (dd, J = 12.8 Hz,2.8 Hz, 2H), 1.47 (t, J = 12.8 Hz, 2H), 1.35 (s, 6H), 1.25 (s, 6H).LCMS: 443.2 [M + H]⁺  42

1-(3,4-difluorophenyl)-2- (2-methoxyphenyl)-4- (2,2,6,6-tetramethyltetrahydro-2H- pyran-4-yl)-1H-imidazole ¹H NMR (400 MHz,DMSO-d₆) δ 7.45(dd, J = 1.6 Hz, 6.0 Hz, 1H), 7.39(m, 2H), 7.30 (m, 2H),7.01(t, J = 2.8 Hz, 1H), 3.07(m, 1H), 1.90 (dd, J = 3.2 Hz, 10.0 Hz,2H), 1.34(t, J = 12.8 Hz, 1H), 1.27 (s, 6H), 1.13 (s, 6H); LCMS: 427.3[M + H]⁺  43

4-(2-(2-methoxypyridin-3- yl)-4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 1-yl)benzonitrile ¹H NMR (400 MHz, DMSO-d₆) δ8.21- 8.19 (m, 1H), 7.96-7.94 (m, 1H), 7.85 (d, J = 8.8 Hz, 2H), 7.39(s, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.12-7.09 (m, 1H), 3.12- 3.08 (m,1H), 1.92- 1.88 (m, 2H), 1.39-1.33 (m, 2H), 1.27 (s, 6H), 1.14 (s, 6H).LCMS: 417.3 [M + H]⁺  44

3-(1-(4-chloro-3- fluorophenyl)- 4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-2-methoxypyridine ¹H NMR (400 MHz,DMSO-d₆) δ 8.20 (m, 1H), 7.91 (dd, J = 8 Hz, 8 Hz, 1H), 7.56 (t, J = 8Hz, 1H), 7.35 (m, 1H), 7.1(m, 1H), 6.94 (dd, J = 12 Hz, 8 Hz, 1H), 3.30(s, 3H), 3.0 (m, 1H), 1.91 (dd, J = 4 Hz, 12 Hz, 2H), 1.36 (t, J = 16Hz, 2H), 1.2(s, 6H), 1.1(s, 6H), LCMS: 444.2 [M + H]⁺  45

1-(3-chloro-4- fluorophenyl)-2-(2- methoxyphenyl)-4- (2,2,6,6-tetramethyltetrahydro-2H- pyran-4-yl)-1H-imidazole ¹H NMR (400 MHz,DMSO-d₆) δ 7.53 (dd, , J = 8 Hz, 8 Hz, 1H), 7.33 (m, 1H), 7.23 (t, J =7.6 Hz, 1H), 7.01(m, 2H), 6.94 (m, 1H), 6.8 (s, 1H), 6.72 (d, J = 12 Hz,1H), 3.30 (s, 3H), 3.22 (m, 1H), 2.04 (d, J = 7.6 Hz, 2H), 1.46 (t, J =12 Hz, 2H), 1.35(s, 6H), 1.25 (s, 6H). LCMS: 443.2 [M + H]⁺  46

3-(1-(3-chloro-4- fluorophenyl)- 4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-2-methoxypyridine ¹H NMR (CDCl₃, 400 MHz)δ 8.17(m, 1H), 7.88(m, 1H), 7.27(m, 1H), 7.06(m, 1H), 6.95(m, 2H),6.92(s, 2H), 3.54(s, J = 12.8 Hz, 3H), 3.219 (m, 1H), 2.02(m, 2H),1.46(m, 2H) 1.35(s, 6H) 1.25(s, 6H); LCMS: 444.2 [M + H]⁺  47

2-(1-(4-fluorophenyl)- 4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-3-methoxypyrazine ¹H NMR (CDCl₃, 400 MHz)δ 8.20 (d, J = 2.4 Hz, 1H), 8.07 (d, J = 4 Hz, 1H), 7.11 (t, J = 8 Hz,2H), 7.0 (t, J = 8 Hz, 2H), 6.96 (s, 1H), 3.6 (s, 3H), 2.05(d, J = 4 Hz,2H), 1.52(d, J = 16 Hz, 2H), 1.35(s, 6H), 1.25(s, 6H). LCMS: 411.2 [M +H]⁺  48

3-(2-(2-methoxypyridin-3- yl)-4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 1-yl)benzonitrile ¹H NMR (CDCl₃, 400 MHz) δ8.18 (t, J = 2 Hz, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 8 Hz,1H), 7.44 (t, J = 10.4 Hz, 2H), 7.33 (d, J = 8 Hz, 1H), 7.01-6.96 (m,2H), 3.44 (s, 3H), 3.23 (t, J = 12.4 Hz, 1H), 2.04-2.01 (dd, J = 12.8Hz, 2.4 Hz, 2H), 1.48 (t, J = 12.8 Hz, 2H), 1.36 (s, 6H), 1.26 (s, 6H).LCMS: 417.3 [M + H]⁺  49

5-(1-(4-chlorophenyl)-4- (2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-4- methoxypyrimidine ¹H NMR (CDCl₃, 400MHz) δ 8.75 (s, 1H), 8.71 (s, 1H), 7.32 (d, J = 8 Hz, 2H), 7.06 (d, J =8.80 Hz, 2H), 6.97 (s, 1H), 3.6 (s, 3H), 3.20- 3.26 (m, 1H), 2.0-2.04(dd, J = 12.8 Hz, 3.2 Hz, 2H), 1.48 (t, J = 12.8 Hz, 2H), 1.36 (s, 6H),1.26 (s, 6H). LCMS: 427.4 [M + H]⁺  50

2-(1-(4-chlorophenyl)-4- (2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-3- methoxypyrazine ¹H NMR (CDCl₃, 400MHz) δ 8.21(d, J = 2.8 Hz, 1H), 8.09(d, J = 2 Hz, 1H), 7.28(t, J = 8.4Hz, 2H), 7.06(d, J = 8.4 Hz, 2H), 6.96 (s, 1H), 3.62 (s, 3H), 3.28 (m,1H), 2.05(dd, J = 12.8 Hz, 12.8 Hz, 2H), 1.49 (t, J = 13.2 Hz, 2H),1.35(s, 6H), 1.25(s, 6H). LCMS: 427.2 [M + H]⁺  51

3-(1-(4-chlorophenyl)-4- (2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-2-ethoxypyridine ¹H NMR (CDCl₃, 400 MHz)δ 8.15-8.14 (m, 1H), 7.92-7.91 (m, 1H), 7.29-7.27 (m, 2H), 7.05 (d, J =8.4 Hz, 2H), 6.96- 6.93 (m, 2H), 3.97 (dd, J = 14, 6.8 Hz, 2H), 3.29-3.21 (m, 1H), 2.04-2.01 (m, 2H), 1.51-1.44 (m, 2H), 1.36 (s, 6H), 1.26(s, 6H), 0.94 (t, J = 6.8 Hz, 3H). LCMS: 440.3 [M + H]⁺  52

3-(1-(3,4-difluorophenyl)- 4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-2-ethoxypyridine ¹H NMR (400 MHz,DMSO-d₆) δ 8.17 (t, J = 3.2 Hz, 1H), 7.94-7.92 (dd, J = 6.8 Hz, 1.2 Hz,1H), 7.46-7.35 (m, 2H), 7.32 (s, 1H), 7.09-7.06 (m, 1H), 6.94 (d, J =8.4 Hz, 1H), 3.90 (q, J = 7.2 Hz, 2H), 3.08 (t, J = 12.4 Hz, 1H),1.92-1.89 (dd, J = 12.8 hz, 2 Hz, 2H), 1.35 (t, J = 12.8 Hz, 2H), 1.27(s, 6H), 1.14 (s, 6H), 0.84 (t, J = 7.2 Hz, 3H). LCMS: 442.3 [M + H]⁺ 53

5-(2-(2-methoxyphenyl)- 4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 1-yl)-2- (trifluoromethyl)pyridine ¹H NMR(CDCl₃, 400 MHz) δ 8.592(s, 1H), 7.61(m, 2H), 7.55(m, 1H) 7.393-7.354(m, 1H), 7.260(s, 1H), 7.07-7.04(m, 1H), 6.989(s, 1H), 6.7195(d, 8.4 Hz,1H), 3.28 (s, 3H), 3.23(m, 1H) 2.05 (m, 2H), 1.51 (m, 2H) 1.36 (s, 6H),1.26(s, 6H); LCMS: 460.3 [M + H]⁺  54

2-methoxy-3-(4-(2,2,6,6- tetramethyltetrahydro-2H- pyran-4-yl)-1-(6-(trifluoromethyl)pyridin- 3-yl)-1H-imidazol-2- yl)pyridine ¹H NMR(CDCl₃, 400 MHz) δ 8.595(d, 2.4 Hz, 1H), 8.20(dd J = 6.8 Hz, 1.6 Hz,1H), 7.99 (dd, J = 9.2 Hz, 2 Hz 1H), 7.66(m, 1H), 7.55(m, 1H), 7.01 (m,2H), 3.435(s, 3H), 3.24 (m, 1H), 2.03(m, 2H), 1.5(m, 2H), 1.369(s, 6H),1.270(s, 6H); LCMS: 461.2 [M + H]⁺  55

1-(4-chlorophenyl)-2- (cyclopropylmethyl)-4- (2,2,6,6-tetramethyltetrahydro-2H- pyran-4-yl)-1H-imidazole ¹H NMR (400 MHz,DMSO-d₆) 7.75 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 6.93 (s,1H), 2.99 (s, 1H), 2.5l (s, 2H), 1.86-1.82 (dd, J = 12.8 Hz, 2.8 Hz,2H), 1.31- 1.25 (m, 8H), 1.11 (s, 6H), 0.85 (m, 1H), 0.32 (d, J = 6.4Hz, 2H),- 0.047 (d, J = 4.4 Hz, 2H). LCMS: 373.3 [M + H]⁺  56

1-(4-chlorophenyl)-2- (cyclopropyl)-4- (2,2,6,6-tetramethyltetrahydro-2H- pyran-4-yl)-1H-imidazole ¹H NMR (CDCl₃, 400MHz) δ 7.44(d, J = 8.8 Hz, 2H), 7.34(d, J = 8.8 Hz, 2H), 6.67(s, 1H),5.29 (s, 1H), 3.0 (m, 1H), 1.93(dd, J = 12.8 Hz, 13.2 Hz, 2H), 1.34(m,1H), 1.70(m, 1H), 1.25(m, 1H), 1.33(s, 6H), 1.22(s, 6H), 1.05(m, 2H),0.87(m, 2H). LCMS: 359.3 [M + H]⁺  57

4-(2-cyclopropyl-4- (2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 1-yl)benzonitrile ¹H NMR (400 MHz, DMSO-d₆) δ7.95 (d, J = 8 Hz, 2H), 7.71 (d, J = 7.6 Hz, 2H), 7.08 (s, 1H), 2.94 (t,J = 12.8 Hz, 1H), 1.80 (t, J = 7.2 Hz, 3H), 1.27-1.21 (s, 8H), 1.10 (s,6H), 0.88- 0.85(m, 4H). LCMS: 350.3 [M + H]⁺  58

4-(2-cyclopropylmethyl)- 4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 1-yl)benzonitrile ¹H NMR (400 MHz, DMSO-d₆) δ =7.99- 7.99(2H, d, J = 0.06 Hz), 7.64-7.62 (2H, d, J = 1.44 Hz), 7.08(1H, s), 3.0(3H, s), 2.59-2.57 (2H, d, J = 0.96 Hz), 1.87-1.83 (2H, dd,J = 2.4 Hz), 1.31- 1.25(2H, d, J = 3.48 Hz), 1.25(6H, s), l.12(6H, s).LCMS: 364 [M + H]⁺  59

5-(2-cyclopropylmethyl)- 4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 1-yl)-2- (trifluoromethyl)pyridine ¹H NMR (400MHz, DMSO-d₆) δ 8.87 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 8.4Hz, 1H), 7.15 (s, 1H), 2.61 (t, J = 6.4 Hz, 1H), 2.06 (d, J = 6.4 Hz,2H), 1.88-1.84 (dd. J = 12.8 Hz, 2.8 Hz, 2H), 1.31 (d, J = 12.8 Hz, 2H),1.26 (s, 6H), 1.26 (s, 6H), 0.89 (m, 1H), 0.35- 0.32 (dd. J = 7.6 Hz,4.4 Hz, 2H), −0.04-−0.04 (dd. J = 10 Hz, 5.2 Hz, 2H). LCMS: 408.5 [M +H]⁺  60

2-(1-(4-chlorophenyl)- 4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-3-ethoxypyrazine ¹H NMR (CDCl₃, 400 MHz)δ 8.23 (d, J = 2.4 Hz, 1H), 8.08 (d, J = 2.8 Hz, 1H), 7.29 (d, J = 8.8Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 6.96 (s, 1H), 4.08-4.02(q, J = 7.2Hz, 2H), 3.31-3.24 (m, 1H), 2.07-2.03 (dd, J = 13.2 Hz, 3.2 Hz, 2H),1.50 (t, J = 13.6 Hz, 2H), 1.35 (s, 6H), 1.25 (s, 6H), 1.02 (t, J = 6.8Hz, 3H). LCMS: 441.3 [M + H]⁺  61

1-(4- (difluoromethoxy)phenyl)- 2-(2-methoxyphenyl)-4- (2,2,6,6-tetramethyltetrahydro-2H- pyran-4-yl)-1H-imidazole ¹H NMR (400 MHz,DMSO-d₆) δ 7.45-7.43 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 7.38-7.33 (m, 1H),7.20 (s, 1H), 7.13 (s, 1H), 7.00 (t, J = 5.2 Hz, 1H), 6.86 (d, J = 8.4Hz, 1H), 3.21 (s, 3H) 3.08 (t, J = 12.8 Hz, 1H), 1.92- 1.88 (dd, J =13.2 Hz, 3.2 Hz, 2H), 1.35 (t, J = 12.8 Hz, 2H), 1.27 (s, 6h), 1.14 (s,6H). LCMS: 457.6 [M + H]⁺  62

1-(4-bromo-3- fluorophenyl)- 2-(2-methoxyphenyl)-4- (2,2,6,6-tetramethyltetrahydro-2H- pyran-4-yl)-1H-imidazole ¹H NMR (CDCl₃, 400MHz) δ 7.56-7.53 (dd, J = 7.6 Hz, 2 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H),7.37-7.33 (m, 1H), 7.02 (t, J = 7.6 Hz, 1H), 6.94- 6.91 (m, 2H),6.08-6.78 (m, 1H), 6.74 (d, J = 8.4 Hz, 1H), 3.36 (s, 3H), 3.22 (t, J =12.8 Hz, 1H), 2.02 (d, J = 2.8 Hz, 2H), 1.47 (t, J = 12.8 Hz, 2H), 1.35(s, 6H), 1.25 (s, 6H). LCMS: 487.2 [M + H]⁺  63

1-(3-bromo-4- fluorophenyl)- 2-(2-methoxyphenyl)-4- (2,2,6,6-tetramethyltetrahydro-2H- pyran-4-yl)-1H-imidazole ¹H NMR (400 MHz,DMSO-d₆)δ 7.49-7.51 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 7.45 (d, J = 7.6 Hz,1H), 7.37 (t, J = 6.8 Hz, 1H), 7.32 (t, J = 8.8 Hz, 1H), 7.27 (s, 1H),7.06- 7.10 (m, 1H), 7.01 (t, J = 7.2 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H),3.26 (s, 3H), 3.04-3.10 (m, 1H), 1.88- 1.92 (dd, J = 13.2 Hz, 3.2 Hz,2H), 1.34 (t, J = 12.8 Hz, 2H), 1.27 (s, 6H), 1.14 (s, 6H). LCMS: 487.2[M + H]⁺  64

3-(1-(3-bromo-4- fluorophenyl)-4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-2-methoxypyridine ¹H NMR (CDCl₃, 400 MHz)δ 8.18-8.16 (dd, J = 4.8 Hz, 2 Hz, 1H), 7.89- 7.87 (dd, J = 7.2 Hz, 1.6Hz, 1H), 7.44-7.42 (dd, J = 6.4 Hz, 2.8 Hz, 1H), 7.06 (m, 3H), 6.92 (s,1H), 3.53 (s, 3H), 3.25- 3.18 (m, 1H), 2.04-2.00 (dd, J = 12.8 Hz, 3.2Hz, 2H), 1.47 (t, J = 12.8 Hz, 2H), 1.35 (s, 6H), 1.25 (s, 6H). LCMS:488.2 [M + H]⁺  65

3-(1-(4-bromo-3- fluorophenyl)-4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-2-methoxypyridine ¹H NMR (CDCl₃, 400 MHz)δ 8.19-8.17 (dd, J = 7.2 Hz, 2 Hz, 1H), 7.90- 7.88 (dd, J = 7.6 Hz, 1.6Hz, 1H), 7.51-7.46 (m, 1H), 6.99-6.93 (m, 3H), 6.79 (d, J = 8.4 Hz, 1H),3.52 (s, 3H), 3.28- 3.22 (m, 1H), 2.04-2.00 (dd, J = 12.8 Hz, 2.8 Hz,2H), 1.54-1.44 (m, 2H), 1.35 (s, 6H), 1.26 (s, 6H). LCMS: 488.2 [M + H]⁺ 66

4-(1-(4-chlorophenyl)- 4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-3-methoxypyridine ¹H NMR (400 MHz,DMSO-d₆)δ 8.30 (d, J = 4.8 Hz, 1H), 8.28 (s, 1H), 7.51 (d, J = 4.8 Hz,1H), 7.44 (d, J = 8.44 Hz, 2H), 7.36 (s, 1H), 7.16 (d, J = 8.8 Hz, 2H),3.33 (s, 3H), 3.11 (t, J = 13.2 Hz, 1H), 1.93-1.89 (m, 2H), 1.36 (t, J =12.4 Hz, 2H), 1.28 (s, 6H), 1.15 (s, 6H). LCMS 426.36 [M + H]⁺  67

2-(1-(4-chlorophenyl)- 4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-3-methoxypyridine ¹H NMR (400 MHz,DMSO-d₆)δ 8.16 (d, J = 3.2 Hz, 1H), 7.45-7.37 (m, 4H), 7.30 (s, 1H),7.09 (d, J = 8.4 Hz, 2H), 3.47 (s, 3H), 1.93-1.89 (m, 2H), 1.40-1.33 (m,2H), 1.29 (s, 6H), 1.15 (s, 6H). LCMS 426.36 [M + H]⁺  68

3-(1-(4-chlorophenyl)- 4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-4-methoxypyridine ¹H NMR (400 MHz,DMSO-d₆) δ 8.50 (s, 1H), 8.66 (d, J = 5.6 Hz, 1H), 7.43 (d, J = 8.8 Hz,2H), 7.33 (s, 1H), 7.17 (d, J = 6.0 Hz, 1H), 3.36 (s, 3H), 3.14-3.08 (m,1H), 1.94-1.89 (m, 2H), 1.4-1.33 (m, 2H), 1.29 (s, 6H), 1.15 (s, 6H).LCMS 426.36 [M + H]⁺  69

3-(1-(4-fluorophenyl)- 4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-4-methoxypyridine ¹H NMR (400 MHz,DMSO-d₆) δ 8.49 (s, 1H), 8.53 (d, J = 5.6 Hz, 1H), 7.3 (s, 1H), 7.20 (d,J = 6.0 Hz, 4H), 6.95 (d, J = 5.2 Hz, 1H), 3.37 (s, 3H), 3.11-3.08 (m,1H), 1.93-1.85(m, 2H), 1.40- 1.37 (m, 2H), 1.29 (s, 6H), 1.15 (s, 6H).LCMS 410.23 [M + H]⁺  70

2-(1-(4-fluorophenyl)- 4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-3-methoxypyridine ¹H NMR (400 MHz,DMSO-d₆) δ 8.12-8.16 (m, 1H), 7.44-7.38 (m, 1H), 7.26 (s, 1H), 7.19-7.09 (m, 4H), 3.47 (s, 3H), 3.14-3.07 (m, 1H), 1.94-1.91 (m, 2H), 1.40-1.37 (m, 2H), 1.34 (s, 6H), 1.15 (s, 6H). LCMS 410.47 [M + H]⁺  71

3-(1-(2,5-difluorophenyl)- 4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-3-methoxypyridine ¹H NMR (400 MHz,DMSO-d₆)δ 8.18 (d, J = 3.2 Hz, 1H), 7.91 (d, J = 5.6 Hz, 1H), 7.43-7.40(m, 1H), 7.29 (br s, 2H), 7.26-7.22 (m, 1H), 7.10- 7.07 (m, 1H), 3.40(s, 3H), 3.12 (m, 1H), 1.91 (d, J = 12.8, 1H), 1.36 (dd, J = 12.8 & 12.8Hz, 1H), 1.29 (s, 6H), 1.15 (s, 6H). LCMS 428.62 [M + H]⁺  72

3-(1-(3,5-difluorophenyl)- 4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-2-methoxypyridine ¹H NMR (400 MHz,DMSO-d₆) δ 8.20 (dd, J = 1.6 & 5.2 Hz, 1H), 7.91 (dd, J = 1.6 & 5.6 Hz,1H), 6.99 (dd, J = 5.2 & 7.2 Hz, 1H), 6.95 (s, 1H), 6.75 (dd, J = 8.4 &8.4 Hz, 1H), 6.68 (d, J = 5.6 Hz, 2H), 3.50 (s, 3H), 3.21 (m, 1H),2.02-2.00 (m, 2H), 1.50-1.43 (m, 2H), 1.35 (s, 6H), 1.20 (s, 6H). LCMS428.51 [M + H]⁺  73

3-fluoro-5-(2-(2- methoxypyridin-3-yl)- 4-(2,2,6,6-tetramethyltetrahydro-2H- pyran-4-yl)-1H-imidazol- 1-yl)benzonitrile ¹HNMR (400 MHz, DMSO-d₆) δ 8.22 (dd, J = 1.6 & 5.2 Hz, 1H), 7.96 (dd, J =1.6 & 5.6 Hz, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.23 (d, J = 4.4 Hz, 1H),7.12 (d, J = 9.2 Hz, 1H), 7.02 (dd, J = 5.2 & 7.2 Hz, 1H), 6.96 (s, 1H),3.50 (s, 3H), 3.22 (m, 1H), 2.02 (dd, J = 2.8 & 13.2 Hz, 2H), 1.50-1.43(m, 2H), 1.36 (s, 6H), 1.20 (s, 6H). LCMS 435.36 [M + H]⁺  75

3-(1-(6-ethoxypyridin-3- yl)-4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 2-yl)-2-methoxypyridine ¹H NMR (400 MHz,DMSO-d₆) δ 8.18- 8.19(m, 1H), 7.94 (d, J = 2.8 Hz, 1H), 7.88-7.91 (m,1H), 7.51-7.54 (m, 1H), 7.27 (s, 1H), 7.07- 7.10 (m, 1H), 6.79 (d, J =9.2 Hz, 1H), 4.23-4.28 (q, 2H), 3.42 (s, 3H), 3.10 (t, J = 13.2 Hz, 1H),1.89-1.93 (m, 2H), 1.36- 1.39 (m, 2H), 1.28- 1.33 (m, 9H), 1.15 (m, 6H)LCMS 437.5[M + H]⁺ 121

4-(2-(2-methoxyphenyl)- 4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 1-yl)-2-(trifluoromethyl) benzonitrile ¹H NMR(400 MHz, DMSO-d₆) δ 8.13 (d, J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.53-7.58(m, 3H), 7.42 (t, J = 7.6 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.88 (d, J= 8.4 Hz, 1H), 3.16 (s, 3H), 3.09-3.13 (m, 1H), 1.90-1.94 (m, 2H),1.32-1.39 (m, 2H), 1.28 (s, 6H), 1.14 (s, 6H). LCMS 453.2 [M + H]⁺ 123

2-chloro-4-(2-(2- methoxyphenyl)- 4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 1-yl)benzonitrile ¹H NMR (DMSO-d₆, 400 MHz) δ7.59 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 6.4 Hz,1H), 7.34 (d, J = 2.0 Hz, 1H), 7.08-7.05 (m, 2H), 6.96 (s, 1H), 6.75 (d,J = 8.4 Hz, 1H), 3.34 (s, 3H), 3.22 (m, 1H), 2.03 (dd, J = 2.4 & 12.8Hz, 2H), 1.50-1.40 (m, 2H), 1.35 (s, 6H), 1.26 (s, 6H). LCMS 450.50 [M +H]⁺ 124*

1-(4-chlorophenyl)-2-(2- methoxyphenyl)- 4-(2,2,6,6-tetramethyl-3,6-dihydro- 2H-pyran-4-yl)-1H- imidazole ¹H NMR ( 400 MHz,CDCl₃) δ 7.62-7.60 (dd, J = 7.6, 1.6 Hz, 1H), 7.36-7.32 (m, 1H), 7.26-7.24 (m, 2H), 7.10 (s, 1H), 7.06-7.00 (m, 3H), 6.71 (d, J = 8.4 Hz, 1H),6.53 (s, 1H), 3.33 (s, 3H), 2.31 (s, 2H), 1.33 (d, J = 6.0 Hz, 12H).LCMS 423.2 [M + H]⁺ 125*

1-(4-bromo-3- fluorophenyl)-2-(2- methoxyphenyl)- 4-(2,2,6,6-tetramethyl-3,6-dihydro- 2H-pyran-4-yl)-1H- imidazole ¹H NMR: (400 MHz,DMSO-d₆) δ 7.66 (t, J = 8.4 Hz, 1H), 7.58 (s, 1H), 7.51-7.49 (m, 1H),7.43- 7.39 (m, 1H), 7.26-7.23 (dd, J = 10 Hz, 2 Hz, 1H), 7.04 (t, J =7.6 Hz, 1H), 6.93-6.87 (m, 2H), 6.33 (s, 1H), 3.28 (d, J = 10 Hz, 3H),2.24 (s, 2H), 1.22 (d, J = 6.8 Hz, 12H) LCMS 485.2 [M + H]⁺ *Compounds124 and 125 were side products obtained while synthesizing compound 38and 62 respectively

Example 8 Compound 74:2-Fluoro-5-[2-(2-methoxy-phenyl)-4-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-imidazol-1-yl]-benzonitrile

To a solution of(3-bromo-4-fluoro-phenyl)-2-(2-methoxy-phenyl)-4-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-1H-imidazole(0.17 g, 0.00034 mol) in DMF (10 mL) was added Zn(CN)₂ (0.08 g, 0.00068mol) under N₂. The reaction mixture was further purged with N₂ for 30min and then stirred for 1 h at 160° C. The reaction was then quenchedwith ice cold water and extracted with ethyl acetate (50 mL×3). Thecombined organic extracts were washed with brine, dried over anhydrousNa₂SO₄, filtered, and concentrated under reduced pressure to provide aresidue. Purification by column chromatography on silica gel (100-200mesh) using ethyl acetate in hexane afforded the title compound 74 as apale yellow solid. Yield: 0.11 g (72.8%). ¹H NMR (CDCl₃, 400 MHz) δ7.54-7.57 (dd, J=5.2Hz, 2.8Hz, 1H), 7.41-7.43 (dd, J=5.2Hz, 2.8Hz, 1H),7.31 - 7.38 (m, 2H), 7.13 (t, J=8.4Hz, 1H), 7.04 (t, J=7.6Hz, 1H), 6.90(s, 1H), 6.73 (d, J=8.4 Hz, 1H), 3.38 (s, 3H), 3.23 (m, 1H), 2.01-2.05(dd, J=12.8Hz, 3.2Hz, 2H), 1.43 - 1.50 (m, 2H), 1.36 (s, 6H), 1.26 (s,6H). LCMS: 487.2 [M+H]⁺.

Using analogous protocols to those described in Example 8, the compoundsdescribed in Table 3 have been prepared using and appropriatelysubstituted bromide intermediate.

TABLE 3 Cpd No. Structure Compound name Analytical data 76

3-fluoro-4-(2-(2- methoxypyridin-3- yl)-4-(2,2,6,6- tetramethyltetra-hydro-2H-pyran-4- yl)-1H-imidazol-1- yl)benzonitrile ¹H NMR (CDCl₃, 400MHz) δ 8.16 (dd, J = 4.8 Hz, 4.8 Hz, 2H), 7.96(dd, J = 1.6 Hz, 7.6 Hz,1H), 7.49(d, J = 4 Hz, 1H), 7.38(d, J = 8 Hz, 1H), 7.17 (t, J = 8 Hz,1H), 6.9 (m, 2H), 3.4 (s, 3H), 3.2 (m, 1H), 2.02(dd, J = 12 Hz, 9.6 Hz,2H), 1.48 (t, J = 12 Hz, 2H), 1.36(s, 6H), 1.26(s, 6H). LCMS: 435.3 [M +H]⁺ 77

2-methoxy-4-(2-(2- methoxypyridin-3- yl)-4-(2,2,6,6- tetramethyltetra-hydro-2H-pyran-4- yl)-1H-imidazol-1- yl)benzonitrile ¹H NMR (CDCl₃, 400MHz) δ 8.2(d, J = 1.6 Hz, 1H), 7.92(d, J = 6.8 Hz, 1H), 7.52(d, J = 8.4Hz, 1H), 6.99 (s, 2H), 6.81(d, J = 1.6 Hz, 1H), 6.65 (s, 1H), 3.70 (m,2H), 3.4 (s, 3H), 3.23(m, 1H), 2.02(d, J = 10.4 Hz, 2H), 1.48 (t, J =12.8 Hz, 2H), 1.36(s, 6H), 1.26(s, 6H). LCMS: 447.3 [M + H]⁺ 78

2-chloro-4-(2-(2- methoxypyridin-3- yl)-4-(2,2,6,6- tetramethyltetra-hydro-2H-pyran-4- yl)-1H-imidazol-1- yl)benzonitrile ¹H NMR (400 MHz,DMSO-d₆)8.23-8.22 (dd, J = 4.8 Hz, 1.6 Hz, 1H), 7.98-7.94 (m, J = 2.6Hz, 1H), 7.48 (s, 1H), 7.24-7.12 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.14-7.11(dd, J = 6.8 Hz, 4.8 Hz, 1H), 3.34 (s, 3H) 3.08 (m, 1H), 1.93-1.89(dd, J= 12.8 Hz, 2.8 Hz, 2H), 1.35 (t, J = 12.8 Hz, 2H), 1.27 (s, 6H). LCMS:451.2 [M + H]⁺ 79

2-fluoro-5-(2-(2- methoxypyridin-3- yl)-4-(2,2,6,6- tetramethyltetra-hydro-2H-pyran-4- yl)-1H-imidazol-1- yl)benzonitrile ¹H NMR (400 MHz,DMSO-d₆)δ 8.19 (d, J = 4.8 Hz, 1H), 7.91 (t, J = 6 Hz, 1H), 7.45-7.43(m, 1H), 7.36-7.32 (m, 1H), 7.18 (t, J = 8.4 Hz, 1H), 7.01-6.98 (m, 1H),6.92 (s, 1H), 3.52 (s, 3H), 3.22 (bs, 1H), 2.03-1.99 (m, 2H), 1.47 (t, J= 12.8 Hz, 3H), 1.36 (s, 6H), 1.26 (s, 6H). LCMS: 435.3 [M + H]⁺ 80

2-fluoro-4-(2-(2- methoxypyridin-3- yl)-4-(2,2,6,6- tetramethyltetra-hydro-2H-pyran-4- yl)-1H-imidazol-1- yl)benzonitrile ¹H NMR (400 MHz,DMSO-d₆) δ 8.22-8.21 (dd, J = 4.8 Hz, 1.6 Hz, 1H), 7.96-7.94 (dd, J =7.6 Hz, 2 Hz, 1H), 7.58 (t, J = 8 Hz, 1H), 7.04- 6.97 (m, 4H), 3.49 (s,3H), 3.25-3.18 (m, 1H), 2.03-1.99 (dd, J = 13.2 Hz, 3.2 Hz, 2H), 1.47(t, J = 12.8 Hz, 2H), 1.36 (s, 6H), 1.26 (s, 7H). LCMS: 435 [M + H]⁺ 81

2-fluoro-4-(2-(2- methoxyphenyl)-4- (2,2,6,6- tetramethyltetra-hydro-2H-pyran-4- yl)-1H-imidazol-1- yl)benzonitrile ¹H NMR (400 MHz,DMSO-d₆)7.06-7.58 (dd, J = 7.2 Hz, 1.6 Hz, 1H), 7.53 (t, J = 8 Hz, 1H),7.41-7.37 (m, 1H), 7.067 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 8.4 Hz, 2H),6.95 (s, 1H), 6.75 (d, J = 8.4 Hz, 1H), 3.34 (s, 3H), 3.26-3.19 (m, 1H),2.05- 2.01 (dd, J = 13.6 Hz, 3.2 Hz, 2H), 1.47 (t, J = 12.8 Hz, 2H),1.35 (s, 6H), 1.25 (s, 6H). LCMS: 434.3 [M + H]⁺ 82

2,6-difluoro-4-(2- (2-methoxypyridin- 3-yl)-4-(2,2,6,6-tetramethyltetra- hydro-2H-pyran-4- yl)-1H-imidazol-1- yl)benzonitrile¹H NMR (CDCl₃, 400 MHz) δ 8.25 (d, J = 3.6 Hz, 1H), 7.96 (d, J = 5.6 Hz,1H), 7.05-7.03(m, 1H), 6.96 (s, 1H), 6.84 (d, J = 8.0 Hz, 2H), 3.56 (s,3H), 3.24-3.18 (m, 1H), 2.02-1.981 (m, 2H), 1.46 (t, J = 12.8 Hz, 2H),1.35 (s, 6H), 1.26 (s, 6H). LCMS: 453.3 [M + H]⁺ 83

3,5-difluoro-4-(2- (2-methoxyphenyl)- 4-(2,2,6,6- tetramethyltetra-hydro-2H-pyran-4- yl)-1H-imidazol-1- yl)benzonitrile ¹H NMR (400 MHz,DMSO-d₆)δ ppm 7.93(d, J = 7.6 Hz, 2H), 7.45 (d, J = 7.2 Hz, 1H), 7.35(t, J = 7.2 Hz, 1H), 7.26 (s, 1H), 7.00 (t, J = 7.6 Hz, 1H), 6.86 (d, J= 8.4 Hz, 1H), 3.31 (s, 3H), 1.91 (d, J = 12.8 Hz, 2H), 1.36 (d, J =12.8 Hz, 2H), 1.28 (s, 6H), 1.14 (s, 6H); LCMS: 452.3 [M + H]⁺ 84

2-chloro-5-(2-(2- methoxypyridin-3- yl)-4-(2,2,6,6- tetramethyltetra-hydro-2H-pyran-4- yl)-1H-imidazol-1- yl)benzonitrile ¹H NMR (400 MHz,DMSO-d₆)δ 8.21(dd, J = 1.2 Hz, 5.2 Hz, 1H), 7.94(dd, J = 8.8 Hz, 9.6 Hz,2H), 7.71(d, J = 8.8 Hz, 1H), 7.41(m, 2H), 7.12(m, 1H), 3.35(s, 3H),3.12(m, 1H), 1.89(d, J = 2.8 Hz, 2H), 1.34(m, 2H), 1.27(s, 6H), 1.14(s,6H). LCMS: 451.2 [M + H]⁺ 85

2-methoxy-5-(2-(2- methoxypyridin-3- yl)-4-(2,2,6,6- tetramethyltetra-hydro-2H-pyran-4- yl)-1H-imidazol-1- yl)benzonitrile ¹H NMR (400 MHz,DMSO-d₆)δ 8.19-8.17 ( dd, J = 4.8 Hz, J2 = 1.6 Hz, 1H), 7.93-7.88 ( m,1H), 7.63 (d, J = 2.4 Hz, 1H), 7.37-7.34 ( dd, J = 8.8 Hz, 2.8 Hz, 1H),7.29 ( s, 1H), 7.18 ( d, J = 9.2 Hz, 1H), 7.09- 7.06 ( m, 1H), 3.88 ( s,3H), 3.39 ( s, 3H), 3.08 ( t, J = 12.8 Hz, 1H), 1.92-1.88 ( dd, J = 12.8Hz, 2.8 Hz, 2H), 1.34 ( t, J = 12.8 Hz, 2H), 1.27 (s, 6H), 1.14 (s, 6H).LCMS: 447.3 [M + H]⁺ 86

4-(2-(4- methoxypyrimidin- 5-yl)-4-(2,2,6,6- tetramethyltetra-hydro-2H-pyran-4- yl)-1H-imidazol-1- yl)benzonitrile ¹H NMR (400 MHz,DMSO-d₆) δ8.81 (s, 1H), 8.74 (s, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.48 (s,1H), 7.41 (d, J = 8.4 Hz, 2H), 3.40 (s, 3H), 3.09-3.15 (m, 1H),1.89-1.93 (dd, J = 12.8 Hz, 2.4 Hz, 2H), 1.36 (t, J = 12.8 Hz, 2H), 1.27(s, 6H), 1.14 (s, 6H). LCMS: 418.3 [M + H]⁺ 87

4-(2-(3- methoxypyrazin-2- yl)-4-(2,2,6,6- tetramethyltetra-hydro-2H-pyran-4- yl)-1H-imidazol-1- yl)benzonitrile ¹H NMR (400 MHz,DMSO-d₆)δ 8.27-8.22 ( dd, J = 18 Hz, 2.8 Hz, 2H), 7.84 ( d, J = 8.4 Hz,2H), 7.48 (s, 1H), 7.30 (d, J = 8.8 Hz, 2H), 3.59 (s, 3H), 3.13 (t, J =12.4 Hz, 1H), 1.93-1.89 (dd, J = 13.6 Hz, 3.2 Hz, 2H), 1.40-1.31 (m,2H), 1.28 (s, 6H), 1.23 (t, J = 4 Hz, 1H), 1.14 (s, 6H). LCMS: 418.3[M + H]⁺ 88

2-fluoro-4-(2-(3- methoxypyrazin-2- yl)-4-(2,2,6,6- tetramethyltetra-hydro-2H-pyran-4- yl)-1H-imidazol-1- yl)benzonitrile ¹H NMR (CDCl₃, 400MHz) δ 8.20 (d, J = 2.4 Hz, 1H), 8.13 (d, J = 2.0 Hz, 1H), 7.59 (t, J =7.2 Hz, 1H), 7.03 (q, J = 10 Hz, 3H), 3.72 (s, 3H), 3.28 (t, J = 12.8Hz, 1H), 2.05-2.02 (m, 2H), 1.54- 1.45 (m, 2H), 1.35 (s, 6H), 1.25 (s,6H). LCMS: 436.2 [M + H]⁺ 89

4-(2-(2- ethoxypyridin-3- yl)-4-(2,2,6,6- tetramethyltetra-hydro-2H-pyran-4- yl)-1H-imidazol-1- yl)-2- fluorobenzonitrile ¹H NMR(CDCl₃, 400 MHz) δ 8.18 (d, J = 4.8 Hz, 1H), 7.94 (d, J = 6.8 Hz, 1H),7.45 (d, J = 3.2 Hz, 1H), 7.36-7.33 (m, 1H), 7.17 (t, J = 8.4 Hz, 1H),6.99 (t, J = 5.2 Hz, 1H), 6.93 (s, 1H), 4.01 (q, J = 6.8 Hz, 2H), 3.22(t, J = 12.4 Hz, 1H), 2.02 (d, J = 13.2 Hz, 2H), 1.51-1.42 ( m, 2H),1.36 (s, 6H), 1.26 (s, 6H), 0.98 (t, J = 6.8 Hz, 3H). LCMS: 449.3 [M +H]⁺

Example 9 Compound 90:1-(4-chlorophenyl)-2-(2-methoxyphenyl)-5-methyl-4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole

To a stirred solution of N-(4-chlorophenyl)-2-methoxybenzimidamide A 38,(0.2 g, 0.07 mmol) and2-bromo-1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)propan-1-one A72(0.3 g, 0.108 mmol) in dioxane (10 mL) was added NaHCO₃ (0.13 g, 0.15mmol). The reaction mixture was refluxed at 100° C. for 12 h. Aftercompletion of the reaction it was filtered through a pad of diatomaceousearth. The resultant filtrate was concentrated under reduced pressure toprovide a crude mixture. Purification by column chromatography on silicagel (100-200 mesh) using ethyl acetate in hexane afforded the titlecompound as an off-white solid. Yield: 0.055 g, 17%. ¹H NMR (400 MHz,DMSO-d₆) 7.45 (d, J=7.2Hz, 1H), 7.28-7.23 (m, 3H), 7.00 (d, J=8.4Hz,2H), 6.93 (t, J=8.0Hz, 1H), 6.64 (d, J=7.6Hz, 1H), 3.37 (s, 3H),3.16-3.18 (m, 1H), 2.11 (s, 3H), 1.87 (t, J=12.8Hz, 2H), 1.75-1.72 (m,2H), 1.36 (s, 6H), 1.26 (s, 6H); LCMS: 439.3 [M+H]⁺.

Example 10 Compound 91:4-(5-chloro-2-(2-methoxypyridin-3-yl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl)benzonitrile

To a solution of4-(2-(2-methoxypyridin-3-yl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl)benzonitrile,Cpd 43, (0.055 g, 0.012 mmol) in acetonitrile (3 mL) was added NCS(0.017 g, 0.013 mmol) at 0° C. The reaction mixture was then heated at80° C. for 5 h. After completion of the reaction, it was quenched withwater and extracted with DCM (2×50 mL). The combined organic extractswere washed with brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure to provide a residue. Purificationby column chromatography on silica gel (100-200 mesh) using ethylacetate in hexane afforded the title compound as a white solid. Yield:0.02 g, 34%. ¹H NMR (CDCl₃, 400 MHz) δ 8.16-8.14 (m, 1H), 7.89-7.86 (m,1H), 7.67 (d, J=8.4Hz, 2H), 7.27-7.25 (m, 1H), 6.97-6.94 (m, 1H), 3.45(s, 3H), 3.34-3.26 (m, 1H), 1.82-1.76 (m, 4H), 1.37 (s, 6H), 1.27 (s,6H); LCMS: 451.2 [M+H]⁺.

Example 11 Compound 92:3-(5-chloro-1-(4-fluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)-2-methoxypyridine

Compound 92 was prepared using the procedure described Example 10 forthe synthesis of Compound 91. ¹H NMR (DMSO, 400 MHz) 8.17 (dd, J=1.6 &4.8 Hz, 1H), 7.88 (dd, J=1.6 & 3.6 Hz, 1H), 7.28-7.24 (m, 4H), 7.07-7.04(m, 1H), 3.46 (s, 3H), 3.18 (m, 1H), 1.75-1.70 (m, 2H), 1.64-1.57 (m,2H), 1.30 (s, 6H), 1.16 (s, 6H); LCMS 444.46 [M+H]⁺.

Example 12 Compound 93:3-(5-chloro-1-(4-chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)-2-methoxypyridine

Compound 93 was prepared using the procedure described Example 10 forthe synthesis of Compound 91. ¹H NMR (DMSO, 400 MHz): 8.12 (d, J=4.8 Hz,1H), 7.81 (dd, J=1.6 & 5.2 Hz, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.07 (d,J=8.4 Hz, 2H), 6.93 (dd, J=5.2 & 7.2 Hz, 1H), 3.51 (s, 3H), 3.32-3.20(m, 1H), 1.90-1.80 (m, 4H), 1.37 (s, 6H), 1.26 (s, 6H); LCMS 460.44[M+H]⁺

Example 13 Compound 94:2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)1((trifluoromethyl)sulfonyl)-1H-imidazole

To a stirred solution of2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole(0.2 g, 0.0006 mol) in DCM (10 mL) at 0° C. was added triethylamine(0.129 g, 0.0012 mol) dropwise over a period of 1 min. The reactionmixture was stirred at 0° C. followed by the addition oftrifluoromethanesulfonic anhydride (0.36 g, 0.0012 mol) and stirred toroom temperature for 12 h. After completion, the reaction was quenchedwith ice cold water, then extracted with ethyl acetate (3×25 mL). Thecombined organic extracts were washed with brine, dried over anhydrousNa₂SO₄, filtered, and concentrated under reduced pressure to provide aresidue. Purification by column chromatography on silica gel (100-200mesh) using ethyl acetate in hexane afforded the title compound as awhite solid. Yield: 37 mg, 24%. ¹H NMR (400 MHz, DMSO-d₆)7.67 (s, 1H),7.50 - 7.55 (m, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H),7.03 (t, J=7.2 Hz, 1H), 3.74 (s, 3H), 3.16 (s, 1H), 1.87 (dd, J=2.8 Hz,J=12.8 Hz, 2H), 1.34 (t, J=12.4 Hz, 2H), 1.26 (s, 6H), 1.14 (s, 6H);LCMS: 447.4 [M+H]⁺.

Example 14 Compound 95:1-(cyclopropylsulfonyl)-2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole

To a stirred solution of2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole(0.1 g 0.00031 mol), in THF (3 mL) was added NaH (0.031 g, 0.00079 mol)portion-wise at 0° C. under a N₂ atmosphere. The reaction mixture wasstirred for 15 min followed by the addition of cyclopropylsulfonylchloride (0.053 g 0.00038 mol) and then the reaction was stirred at rtfor 16 h. The reaction mixture was cooled and quenched with water,extracted with ethyl acetate (2×20mL). The combined organic extractswere washed with brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure to provide a residue. Purificationby column chromatography on silica gel (100-200 mesh) using ethylacetate in hexane afforded the title compound as a white solid. Yield:0.012 g, 10%. ¹H NMR (400 MHz,DMSO-d₆) δ 7.42 (t, J=7.6Hz, 1H), 7.20 (d,J=7.2Hz, 1H), 7.03 (d, 2H), 6.95(t, J=7.6Hz, 1H), 3.70 (s, 3H), 3.27(s,1H), 1.89 (s, 2H), 1.25 - 1.15 (m, 19H); LCMS 419.2 [M+H]⁺.By using analogous protocols to those described in the foregoingexample, the compounds described in Table 4 have been prepared, usingappropriately substituted aryl or alkyl sulfonyl chlorides or ofsulfonic anhydrides.

TABLE 4 Cpd No. Structure Compound name Analytical data 96

1-(isobutylsulfonyl)- 2-(2-methoxyphenyl)- 4-(2,2,6,6- tetramethyltetra-hydro-2H-pyran-4- yl)-1H-imidazole ¹H NMR (CDCl₃, 400 MHz) δ 7.46-7.42(m, 1H), 7.35-7.33 (m, 1H), 7.14 (s, 1H), 7.02 (t, J = 7.6 Hz, 1H), 6.94(d, J = 8.4 Hz, 1H), 3.80 (s, 3H), 3.19-3.12 (m, 3H), 2.20- 2.14 (m,1H), 2.01- 1.97 (m, 2H), 1.45-1.39 (m, 2H), 1.33 (s, 6H), 1.25 (s, 6H),1.02 (d, J = 6.4 Hz, 6H). LCMS: 435.3 [M + H]⁺ 97

1-((4- chlorophenyl)sulfonyl)- 2-(2-methoxyphenyl)- 4-(2,2,6,6-tetramethyltetrahydro- 2H-pyran-4-yl)-1H- imidazole ¹H NMR (400 MHz,DMSO-d₆)δ 7.6 (d, J = 8.8 Hz, 2H), 7.50 (s, 1H), 6.59 (s, 1H), 7.40(t, J= 7.2 Hz, 1H), 7.05-6.94 (m, 3H), 3.45(s, 3H), 1.03(t, J = 12.0 Hz, 1H),1.84(dd, J = 2.8 Hz, 2.4 Hz, 2H), 1.29 (d, J = 12 Hz, 2H) 1.23(s, 6H),1.12 (s, 6H): LCMS: 489.2 [M + H]⁺ 98

1-((4- fluorophenyl)sulfonyl)- 2-(2-methoxyphenyl)- 4-(2,2,6,6-tetramethyltetrahydro- 2H-pyran-4-yl)-1H- imidazole ¹H NMR (CDCl₃, 400MHz) δ 7.69-7.66 (m, 2H), 7.50 (s, 1H), 7.49- 7.42 (m, 3H), 7.04 (m,3H), 7.05-6.94 (m, 3H), 3.47 (s, 3H), 3.02 (s, 1H), 1.84 (dd, J = 2.8Hz, 2.4 Hz, 2H), 1.30- 1.23(m, , 9H), 1.10 (s 6H): LCMS: 473.3 [M + H]⁺

Example 15 Compound 99:4-((2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl)methyl)benzonitrile

To a stirred solution of2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole(0.1 g, 0.00031 mol), in THF was added NaH (0.031 g, 0.000791 mol)portion- wise at 0° C. under a N₂ atmosphere. The reaction mixture wasstirred for 15 min followed by the addition of 4-cyanobenzyl bromide(0.074 g, 0.00034 mol). The reaction was then stirred at rt for 16 h.The reaction mixture was cooled and quenched with water, and extractedwith ethyl acetate (2×20 mL). The combined organic extracts were washedwith brine, dried over anhydrous Na₂SO₄, filtered, and concentratedunder reduced pressure to provide a residue. Purification by columnchromatography on silica gel (100-200 mesh) using ethyl acetate inhexane afforded the title compound as white solid. (0.081 g, 59.5%). ¹HNMR (CDCl₃, 400 MHz) δ 7.59 (d, J=8.4Hz, 2H), 7.41 - 7.36 (m, 2H), 7.14(d, J=8.0Hz, 2H), 7.01(t, J=7.6Hz, 1H), 6.85 (d, J=8.4Hz, 1H), 6.60 (s,1H), 4.90(s, 2H), 3.60(s, 3H), 3.10(t, J=12.8Hz, 1H), 2.0 (dd, J=2.4Hz,2.0Hz, 2H), 1.23(s, 6H), 1.13(s, 6H); LCMS: 430.5 [M+H]⁺.

By using analogous protocols to those described in the foregoing examplethe compounds described in Table 5 have been prepared usingappropriately substituted bromide compounds.

TABLE 5 Cpd No. Structure Compound name Analytical data 100

5-((2-(2- methoxyphenyl)- 4-(2,2,6,6- tetramethyltetra- hydro-2H-pyran-4-yl)-1H- imidazol-1- yl)methyl) pyrimidine ¹H NMR (CDCl₃, 400 MHz) δ9.13 (s, 1H), 8.4(s 2H), 7.51-7.39 (m, 2H), 7.03 (t, J = 15.2 Hz, 1H),6.93 (d, J = 8.4 Hz, 1H), 6.65 (s, 1H), 3.6 (s, 3H), 3.10(t, J = 12.8Hz, 1H) 1.98 (dd, J = 12.8 Hz, 2H) 1.40 (t, 2H), 1.30(s, 6H), 1.23(s,6H): LCMS: 407.2 [M + H]⁺ 101

3-((2-(2- methoxyphenyl)- 4-(2,2,6,6- tetramethyltetra- hydro-2H-pyran-4-yl)-1H- imidazol-1- yl)methyl) benzonitrile ¹H NMR (CDCl₃, 400 MHz) δ7.56 (d, J = 8.0 Hz, 1H), 7.43-7.25 (m, 5H), 7.01 (t, J = 7.6 Hz, 1H),6.92(d, J = 8.8 Hz, 1H), 6.60 (s, 1H), 6.60 (s, 1H), 4.90 (s, 2H), 3.60(s, 3H), 3.1(t, J = 12.8 Hz, 1H), 2.0 (dd, J = 2.4 Hz, 2.0 Hz, 2H),1.53-1.37 (m, 2H), 1.3(s, 6H), 1.23 (s, 6H): LCMS: 430.5 [M + H]⁺

Example 16 Compound 102:4-(1-(4-chlorophenyl)-2-(2-methoxyphenyl)-1H-imidazol-4-yl)-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol

To a stirred solution of N-(4-chlorophenyl)-2-methoxybenzimidamide A 39(0.37 g, 0.0014 mol) in dioxane (15 mL) was added2-bromo-1-(4-hydroxy-2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-ethanoneA 75 (0.4 g, 0.0014 mol) and NaHCO₃ (0.24 g, 0.00286 mol) and themixture was stirred for 5 h at 85° C. The solvent was evaporated and theresultant crude residue was partitioned between ethyl acetate and water.The combined organic extracts were washed with brine, dried overanhydrous Na₂SO₄, filtered, and concentrated under reduced pressure toprovide a residue. Purification by column chromatography on silica gel(100-200 mesh) using ethyl acetate in hexane afforded the title compoundas a pale yellow solid. Yield: 0.12 g, 20%. ¹H NMR (400 MHz, DMSO-d₆)7.47 -7.45(m, 1H), 7.40-7.35 (m, 3H), 7.26(s, 1H), 7.09 (d, J=8.8Hz,2H), 7.01 (t, J=7.6Hz, 1H), 6.87 (d, J=8.4Hz, 1H), 4.82 (s, 1H), 3.21(s, 3H), 1.87-1.76 (m, 4H), 1.44 (s, H), 1.10 (s, 6H); LCMS: 441.2[M+H]⁺.

By using analogous protocols to those described in the foregoing examplethe compounds described in Table 6 have been prepared using anappropriately substituted amidine intermediate.

TABLE 6 Cpd No. Structure Compound name Analytical data 103

4-(1-(4-chlorophenyl)- 2-(4-methoxypyridin- 3-yl)-1H-imidazol-4-yl)-2,2,6,6- tetramethyltetra- hydro-2H-pyran-4-ol ¹H NMR (400 MHz,DMSO-d₆) δ = 8.51 (s, 1H), 8.47 (d, J = 5.6 Hz, 1H), 7.44 (d, J = 8.4Hz, 2H), 7.36 (s, 1H), 7.17 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 5.6 Hz,1H), 4.92 (s, 1H), 3.35 (s, 3H), 1.86 (d, J = 13.2 Hz, 2H), 1.80 (d, J =13.2 Hz, 2H), 1.46 (s, 6H), 1.12 (s, 6H). LCMS: 442.44 [M + H]⁺ 104

4-(1-(4-chlorophenyl)- 2-(3-methoxypyridin- 2-yl)-1H-imidazol-4-yl)-2,2,6,6- tetramethyltetrahydro- 2H-pyran-4-ol ¹H NMR (400 MHz,DMSO-d₆) δ = 8.19 (s, 1H), 7.38-7.44 (m, 4H), 7.32 (s, 1H), 7.08 (d, J =7.6 Hz, 2H), 4.94 (s, 1H), 3.44 (s, 3H), 1.77- 1.87 (m, 4H), 1.46 (s,6H), 1.11 (s, 6H). LCMS: 442.48 [M + H]⁺ 105

4-(1-(4-chlorophenyl)- 2-(2-methoxypyridin- 3-yl)-1H-imidazol-4-yl)-2,2,6,6- tetramethyltetrahydro- 2H-pyran-4-ol ¹H NMR (400 MHz,DMSO-d₆) δ = 8.20 (d, J = 8 Hz, 1H), 7.93 (d, J = 7.2 Hz, 1H), 7.45 (d,J = 8.4 Hz, 2H), 7.34 (s, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.10 (t, J =6.8 Hz, 1H), 4.93 (s, 1H), 3.34 (s, 3H), 1.77-1.87 (m, 4H), 1.46 (s,6H), 1.11 (s, 6H). LCMS: 442.44 [M + H]⁺ 106

4-(1-(3-bromo-4- fluorophenyl)-2-(2- methoxyphenyl)-1H- imidazol-4-yl)-2,2,6,6- tetramethyltetrahydro- 2H-pyran-4-ol ¹H NMR (400 MHz, DMSO-d₆)δ 7.46 (d, J = 8.0 Hz, 2H), 7.34- 7.40 (m, 2H), 7.31 (s, 1H), 7.08-7.12(m, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 4.80 (s,1H), 3.25 (s, 3H), 1.80-1.82 (m, 4H), 1.44 (s, 6H), 1.22 (s, 6H). LCMS:453.2 [M + H]⁺ 107

4-(1-(3,4- difluorophenyl)-2-(2- methoxyphenyl)-1H- imidazol-4-yl)-2,2,6,6- tetramethyltetrahydro- 2H-pyran-4-ol ¹H NMR (400 MHz, DMSO-d₆)δ 7.47 (m, 1H), 7.48 (m, 2H), 7.26 (m, 2H), 7.02(t, J = 8 Hz, 1H), 6.89(m, 2H), 4.8 (s, 1H), 3.2 (s, 3H), 1.81 (m, 4H), 1.44(s, 6H), 1.10(s,6H). LCMS: 443.3[M + H]⁺ 108

4-(1-(3,4- difluorophenyl)-2-(2- methoxypyridin-3- yl)-1H-imidazol-4-yl)-2,2,6,6- tetramethyltetrahydro- 2H-pyran-4-ol ¹H NMR (400 MHz,DMSO-d₆) δ 7.48(d, J = 7.6 Hz, 1H), 7.39 (t, J = 8 Hz, 1H), 7.34 (s,1H), 7.2 (dd, J = 8 Hz, 10.4 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.92 (t,J = 12 Hz, 1H), 4.8 (s, 1H), 3.2 (s, 3H), 1.81 (m, 4H), 1.1(s, 6H),1.4(s, 6H). LCMS: 444.2 [M + H]⁺ 109

4-(2-(2- methoxyphenyl)-1- (6-(trifluorometh- yl)pyridin-3-yl)-1H-imidazol-4- yl)-2,2,6,6- tetramethyltetrahydro- 2H-pyran-4-ol ¹HNMR (400 MHz, DMSO-d₆) δ 8.574(s, 1H), 7.93(d, J = 8.4 Hz, 1H), 7.804(d, J = 10.4 Hz, 1H), 7.57(d, J = 6 Hz, 1H), 7.516 (s, 1H), 7.430 (m,1H), 7.101(m, 1H), 6.898(d, J = 8.4 Hz, 1H), 4.937(s, 1H), 3.16(s, 3H),1.85(m, 4H), 1.47(s, 6H), 1.13 (s, 6H); LCMS: 476.3 [M + H]⁺ 110

4-(1-(3-chloro-4- fluorophenyl)-2-(2- methoxypyridin-3-yl)-1H-imidazol-4-yl)- 2,2,6,6- tetramethyltetrahydro- 2H-pyran-4-ol ¹H NMR(400 MHz, DMSO-d₆) δ 8.19(t, J = 7.2 Hz, 2H), 7.91(m, 1H), 7.46 (m, 1H),7.42 (d, J = 8.0 Hz, 1H), 7.36 (s, 1H), 7.11 (m, 2H), 4.85(s, 1H),3.37(s, 3H), 1.81(dd, J = 13.6 Hz, 5.2 Hz, 4H), 1.44(s, 6H), 1.10(s,6H): LCMS: 460.2 [M + H]⁺ 111

4-(1-(3-chloro-4- fluorophenyl)-2-(2- methoxyphenyl)-1H-imidazol-4-yl)-2,2,6,6- tetramethyltetrahydro- 2H-pyran-4-ol ¹H NMR (400MHz, DMSO-d₆) δ 7.5 (d, J = 6 Hz, 1H), 7.40-7.39 (m, 3H), 6.20 (s, 1H),7.09-7.01(m, 2H), 6.80 (d, J = 8.4 Hz, 1H), 4.80 (s, 1H), 3.25 (s, 3H),1.86-1.77(m, 4H), 1.44 (s, 6H), 1.10 (s, 6H): LCMS: 459.2 [M + H]⁺ 112

4-(1-(4-chloro-3- fluorophenyl)-2-(2- methoxyphenyl)-1H-imidazol-4-yl)-2,2,6,6- tetramethyltetrahydro- 2H-pyran-4-ol ¹H NMR (400MHz, DMSO-d₆) δ 7.53(t, J = 12 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.40(t, J = 8 Hz, 1H), 7.34 (s, 1H), 7.2 (dd, J = 10 Hz, 10.4 Hz, 1H), 7.01(t, J = 8 Hz, 1H), 6.90 (t, J = 8 Hz, 2H), 4.8 (s, 1H), 3.2 (s, 3H),1.81 (m, 4H), 1.44(s, 6H), 1.10(s, 6H). LCMS: 459.2 [M + H]⁺ 113

4-(1-(4-chloro-3- fluorophenyl)-2-(2- methoxypyridin-3-yl)1H-imidazol-4-yl)- 2,2,6,6- tetramethyltetrahydro- 2H-pyran-4-ol ¹H NMR(400 MHz, DMSO-d₆) δ 8.20 (t, J = 4 Hz, 1H), 7.93 (dd, , J = 8 Hz, 8 Hz,1H), 7.58 (t, J = 8 Hz, 1H), 7.38 (s, 1H), 7.31 (d, J = 1.6 Hz, 1H),7.10 (m, 1H), 6.96 (d , J = 8 Hz, 1H), 4.8 (s, 1H), 3.3 (s, 3H), 1.81(m, 4H), 1.44(s, 6H), 1.10(s, 6H). LCMS: 460.2 [M + H]⁺ 114

4-(1-(4-chlorophenyl)- 2-(2-ethoxypyridin-3- yl)-1H-imidazol-4-yl)-2,2,6,6- tetramethyltetrahydro- 2H-pyran-4-ol ¹H NMR (400 MHz, DMSO-d₆):8.17(d, J = 3.2 Hz, 1H), 7.93(d, J = 5.6 Hz, 1H), 7.43 (d, J = 8.4 Hz,2H), 7.33(s, 1H), 7.15 (d, J = 8.8 Hz, 2H), 7.07 (m, 1H), 4.86 (s, 1H),3.86 (q, J = 2.8 Hz, 2H), 1.82 (q, J = 12.8 Hz, 4H), 1.44 (s, 6H), 1.26(s, 2H), 1.15 (s, 6H), 0.80 (q, J = 5.6 Hz, 3H). LCMS: 456.3 [M + H]⁺115

4-(4-(4-hydroxy- 2,2,6,6- tetramethyltetrahydro- 2H-pyran-4-yl)-2-(2-methoxypyridin-3-yl)- 1H-imidazol-1- yl)benzonitrile ¹H NMR: (400 MHz,DMSO-d₆): 8.21-8.19 (m, 1H), 7.98-7.95 (m, 1H), 7.86 (d, J = 8.4 Hz,2H), 7.42 (s, 1H), 7.32 (d, J = 8.8 Hz, 2H), 7.13- 7.10 (m, 1H), 4.90(s, 1H), 1.89-1.77 (m, 4H), 1.45 (s, 6H), 1.10 (s, 6H). LCMS: 433.3 [M +H]⁺

Example 17 Compound 116: 2-Fluoro-5-[4-(4-hydroxy-2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-2-(2-methoxy-phenyl)-imidazol-1-yl]-benzonitrile

Step 1. Compound 126.2-Fluoro-5-(2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl)-1H-imidazol-1-yl)benzonitrile.To a stirred solution of4-[1-(3-bromo-4-fluoro-phenyl)-2-(2-methoxy-phenyl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyl-tetrahydro-pyran-4-ol,(0.16 g, 0.000635 mol) in DMF (5 mL) under an N₂ atmosphere was addedZn(CN)₂ (0.075 g, 0.00212 mol) and tetrakis-triphenylphosphine palladium(0.184 g, 0.00015 mol), purging with nitrogen for 15 min before eachaddition. The reaction mixture was further purged for 5 min and stirredfor 1.5 h at 160° C. The reaction mixture was quenched with ice coldwater and extracted with ethyl acetate (50 mL×3). The combined organicextracts were washed with brine, dried over anhydrous Na₂SO₄, filtered,and concentrated under reduced pressure to provide a residue.Purification by column chromatography on silica gel (100-200 mesh) usingethyl acetate in hexane afforded the title compound as a white solid.(0.09 g, 63.3%), LCMS: 432.3 [M+H]⁺.

Step 2. Compound 116:2-Fluoro-5-[4-(4-hydroxy-2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-2-(2-methoxy-phenyl)-imidazol-1-yl]-benzonitrile.To a stirred solution of2-fluoro-5-[2-(2-methoxy-phenyl)-4-(2,2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl)-imidazol-1-yl]-benzonitrile(0.09 g, 0.000208 mol), and Mn(tmhd)₃ (0.025 g, 0.0004172 mol) in i-PrOH(7 mL) and DCM (1 mL) at 0° C., phenylsilane (0.045 g, 0.000417 mol) wasadded and the reaction mixture was stirred for 3 h from 0° C. to rtunder an oxygen atmosphere. Saturated Na₂S₂O₃ solution (2 mL) was addedand the mixture was stirred for 2 h. The reaction mixture was furtherdiluted with brine (10 mL) and extracted with ethyl acetate (10 mL×3).The combined organic extracts were dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure to provide a residue.Purification by column chromatography on silica gel (100-200 mesh) usingethyl acetate in hexane afforded the title compound as an off whitesolid (0.05 g, 56%). ¹H NMR (CDCl₃, 400 MHz) δ 7.54-7.56 (dd, J=7.6 Hz,1.2 Hz, 1H), 7.38 - 7.43 (m, 2H), 7.31 - 7.36 (m, 2H), 7.14 (t, J=8.8Hz,1H), 7.05 (t, J=8.0Hz, 1H), 7.02 (s, 1H), 6.74 (d, J=8.4Hz, 1H), 3.38(s, 3H), 2.06 (d, J=13.2Hz, 2H), 1.90 (d, J=13.6Hz, 2H), 1.56 (s, 6H),1.26 (s, 6H). LCMS: 450.3.2 [M+H]⁺

By using analogous protocols to those described in the foregoing examplethe compounds described in Table 7 have been prepared usingappropriately substituted bromide intermediate.

TABLE 7 Cpd No. Structure Compound name Analytical data 117

2-fluoro-5-(4-(4- hydroxy-2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-2-(2- methoxyphenyl)-1H- imidazol-1- yl)benzonitrile ¹HNMR (CDCl₃, 400 MHz) δ 7.54-7.56 (dd, J = 7.6 Hz, 1.2 Hz, 1H), 7.38-7.43(m, 2H), 7.31-7.36 (m, 2H), 7.14 (t, J = 8.8 Hz, 1H), 7.05 (t, J = 8.0Hz, 1H), 7.02 (s, 1H), 6.74 (d, J = 8.4 Hz, 1H), 3.38 (s, 3H), 2.06 (d,J = 13.2 Hz, 2H), 1.90 (d, J = 13.6 Hz, 2H), 1.56 (s, 6H), 1.26 (s, 6H).LCMS: 450.3 [M + H]⁺ 118

2-fluoro-4-(4-(4- hydroxy-2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-2-(2- methoxyphenyl)-1H- imidazol-1- yl)benzonitrile ¹HNMR: (400 MHz, DMSO-d₆): δ 7.89 (t, J = 8.0 Hz, 1H), 7.52 (d, J = 7.2Hz, 1H), 7.43-7.40 (m, 2H), 7.35 (d, J = 10 Hz, 1H), 7.07 (t, J = 7.6Hz, 2H), 6.90 (d, J = 8.4 Hz, 1H), 4.88 (s, 1H), 3.22 (s, 3H), 1.85-1.77(m, 4H), 1.44 (s, 6H), 1.10 (s, 6H). LCMS: 450.3 [M + H]⁺ 119

2-fluoro-4-(4-(4- hydroxy-2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)-2-(2- methoxypyridin-3- yl)-1H-imidazol-1-yl)benzonitrile ¹H NMR: (400 MHz, DMSO-d₆): δ 8.24- 8.22 (dd, J = 4.8Hz, 1.6 Hz, 1H), 7.99- 7.97 (dd, J = 7.2 Hz, 1.6 Hz, 1H), 7.93 (t, J = 8Hz, 1H), 7.48 (s, 1H), 7.44 (d, J = 1.6 Hz, 1H), 7.34 (bs, 1H),7.15-7.12 (m, 2H), 4.92 (s, 1H), 3.33 (s, 3H), 1.85-1.77 (m, 4H), 1.45(s, 6H), 1.10 (s, 6H). LCMS: 451.3 [M + H]⁺ 120

4-(1-(4-chlorophenyl)- 2-(3- methoxypyridin-4- yl)-1H-imidazol-4-yl)-2,2,6,6- tetramethyltetrahydro- 2H-pyran-4-ol ¹H NMR (DMSO-d₆, 400MHz): 8.31-8.27 (m, 2H), 7.52 (d, J = 4.4 Hz, 1H), 7.44 (d, J = 18.4 Hz,2H), 7.38 (s, 1H), 7.16 (d, J = 8.8 Hz, 2H), 3.32 (s, 3H) 4.95 (s, 1H),1.87- 1.84 (m, 4H), 1.46 (s, 6H), 1.11 (s, 6H). MS: ESI-MS, m/z 442.19(M + 1).

Example 18 Compound 122:3-(1-(4-chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)pyridin-2(1H)-one

To a stirred solution of3-(1-(4-chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)-2-methoxypyridine(320 mg) was added aqueous HBr (47%) 2 mL at 0-5° C., and the mixturewas stirred at rt for 16 h. The reaction was quenched with 10% NaHCO₃solution(30m1), extracted with 10% MeOH in DCM (2×50 mL). The combinedorganic extracts were dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure to provide a residue. Purificationby column chromatography on silica gel (100-200 mesh) using a mixture ofMeOH and DCM afforded the title compound as an off white solid. Yield:0.015 g (48.5%); LCMS 412.2 [M+H]⁺

The compounds of Table 8, exemplified hereinbelow, were preparedaccording to the schemes and specific examples described herein.

TABLE 8 Compounds of Formula (I) Cpd No. Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

BIOLOGICAL EXAMPLES In Vitro Assays Example 1 Functional Assay: CalciumInflux Assay

A Ca flux assay using Functional Drug Screening System (FDSS, Hamamatsu)was utilized to identify novel N-type Ca channel antagonists (Dai et al2008, Beladredetti et al 2009). All cell culture reagents were procuredfrom HyClone and other reagents were from Fisher. Recombinant HEK 293cells expressing human N-type Ca channel (Millipore) were maintained inDMEM F12 containing 10% FBS and selection antibiotics at 37° C. in 5%CO₂.

When CaV2.2 cells were 75%-85% confluent in their culture flask, theywere removed from the flask, counted, and plated at 13,000-15,000 cells(50 μL) per well in black-wall clear-bottom 384-well assay plates. Cellswere incubated at 30° C. in 5% CO₂ overnight. The medium was removed andcells were loaded with Fluo8 dye (AAT Bioquest) at 37° C. and 30° C., 30min each in darkness. Cells were washed four times with wash buffer (16mM Herep pH 7.2, 2 mM CaCl₂, 1 mM MgCl₂, 5 mM glucose, 140 mM cholinechloride and 2 mM KCl) leaving 15 μL buffer after the last wash.Compounds of Formula (I), serially diluted, were added to the cellplate. The plates were incubated in darkness for 15 min. Cells weredepolarized with 100 mM KCl and Ca influx was measured. Data was plottedas percent inhibition vs concentration of the compound and IC₅₀ valueswere generated using Graphpad Prism non-linear regression analysis.Resultant data are shown in Table 9.

Example 2 Measurement of Electrophysiological Response

The recombinant cell line described above was used in the measurement ofelectrophysiological properties with QPatch (Sophion). Cells weremaintained in culture as mentioned above. Prior to the experiment, theflasks were moved to 30° C. and incubated for 48-72 hrs. On the day ofassaying, cells were detached and harvested. The cell pellet wasre-suspended in SMF4HEK (HyClone)/25 mM HEPS at 2-5 million/mL andplaced on the QStirrer of the QPatch for 30-60 min prior to the start ofthe assay. The Intracellular Buffer contained 97.9 mM CsCl, 27 mM CsF,8.2 mM EGTA, 10 mM HEPES, 2 mM NaCl, 0.3 mM GTP, 3 mM Mg-ATP pH ˜7.3adjusted with CsOH and ˜280 mOsm. Extracellular buffer contained 132 mMNaCl, 5.4 mM KCl, 1.8 mM CaCl₂, 0.8 mM MgCl₂, 10 mM HEPES, 10 mM glucosepH ˜7.4 adjusted with NaOH/HCl and ˜300 mOsm. Microtiter-Plate/ReferenceBuffer contained 140 mM TEA-Cl, 10 mM BaCl₂, 0.8 mM MgCl₂, 10 mM HEPESpH ˜7.4 adjusted with TEA-OH/HCl, and ˜300 mOsm. Cells were transferredto a QPatch 48 plate and gigaseal was formed. The plate was perfusedwith intracellular and extracellular buffer. Compounds diluted inreference buffer were applied to the extracellular site and testedfollowing the voltage protocol as described by Finley et al (2010). Inbrief, cells were depolarized from resting potential of −80 mV to +20 mVand current was recorded. Data was plotted as percent inhibition vsconcentration of the compound and IC₅₀ values were generated usingGraphpad Prism non-linear regression analysis. Resultant data isreported in Table 9. Concentration ranges for each compound are includedwith its Q patch value.

TABLE 9 FDSS and Q patch Assay Data Cpd N Type IC₅₀ Data (μM) No. FDSSQpatch Pulse = 1 Qpatch Pulse = 15 1 0.041 0.365 (0.01-1 μM) >1 (0.01-1μM) 2 0.128 NE (10 μM) 6.2 (0.3-10 μM) 3 0.376 0.830 (0.01-1 μM) NE(0.01-1 μM) 4 0.017 10 (0.3-10 μM) 1.06 (0.3-10 μM) 5 0.191 5.9 (0.3-10μM) 10 (0.3-10 μM) 6 0.739 10 (0.3-10 μM) 10 (0.3-10 μM) 7 0.113 1.17(0.3-10 μM) 0.68 (0.3-10 μM) 8 >10 0.508 (0.01-1 μM) >1 (0.01-1 μM) 90.793 46% (0.01-1 μM) 37% (0.01-1 μM) 10 0.401 5.92 (0.3-10 μM) 1.47(0.3-10 μM) 11 0.082 63% (10 μM) 21% (10 μM) 12 0.63 28% (10 μM) NE (10μM) 13 0.2 >1 (0.01-1 uM) NE (0.01-1 μM) 14 2.7 0.266 (0.01-1 μM) >1(0.01-1 μM) 15 0.256 poor fit(0.01-0.3 μM) poor fit(0.01-0.3 μM) 160.359 poor fit(0.01-0.3 μM) poor fit(0.01-0.3 μM) 17 0.591 4.4 (0.3-10μM) 5.2 (0.3-10 μM) 18 0.108 0.694 (0.01-1 μM) 0.376 (0.01- 1 μM) 190.263 0.966 (0.01-1 μM) 28% (1 μM) 20 1.06 >1 (0.01-1 μM) NE (0.01-1 μM)21 0.119 0.639 (0.01-1 μM) 39% (0.01-1 μM) 22 0.075 0.590 (0.01-1 μM)0.847 (0.01-1 μM) 23 0.31 21% (0.01-1 μM) NE (0.01-1 μM) 24 7.15 29%(0.01-1 μM) NE (0.01-1 μM) 25 0.818 >1 (0.01-1 μM) NE (0.01-1 μM) 265.76 >1 (0.01-1 μM) >1 (0.01-1 μM) 27 6.4 poor fit(0.01-0.3 μM)1.9(0.01-0.3 μM) 28 1.64 poor fit(0.01-0.3 μM) poor fit(0.01-0.3 μM) 290.492 poor fit(0.01-0.3 μM) poor fit(0.01-0.3 μM) 30 0.321 67% (10 μM)35% (10 μM) 31 0.769 1.58(0.01-0.3 μM) poor fit(0.01-0.3 μM) 32 0.278 >1(0.01-1 μM) NE (0.01-1 μM) 33 0.459 >1 (0.01-1 μM) NE (0.01-1 μM) 341.62 38% (0.01-1 μM) NE (0.01-1 μM) 35 0.838 NA NA 36 0.04 0.376 (0.01-1μM) NE (0.01-1 μM) 37 0.424 NE (0.01-1 μM) NE (0.01-1 μM) 38 0.372 2.4(0.3-10 μM) 0.769 (0.3-10 μM) 39 0.163 1.7 (0.3-10 μM) 1.9 (0.3-10 μM)40 0.822 52% (10 μM) 1.94 (0.3-10 μM) 41 0.131 71% (10 μM) 0.602 (0.3-10μM) 42 0.194 2.6 (0.3-10 μM) 1.08 (0.3-10 μM) 43 0.291 34% (10 μM) 7.5(0.3-10 μM) 44 0.142 2.9 (0.3-10 μM) 3.08 (0.3-10 μM) 45 0.149 2.2(0.3-10 μM) 0.671 (0.3-10 μM) 46 0.255 10 (0.3-10 μM) 2.5 (0.3-10 μM) 471.54 >1 (0.01-1 μM) NE (0.01-1 μM) 48 5.41 0.222(0.01-1 μM) 0.843(0.01-1 μM) 49 0.123 >1 (0.01-1 μM) NE (0.01-1 μM) 50 0.215 >1 (0.01-1μM) 0.971 (0.01-1 μM) 51 0.029 0.179 (0.01-1 μM) 0.701 (0.01-1 μM) 520.115 0.721 (0.01-1 μM) NE (0.01-1 μM) 53 0.096 6.5 (0.3-10 μM) 2.01(0.3-10 μM) 54 1.96 0.302 (0.01-1 μM) 0.237 (0.01-1 μM) Poor fit(0.01-1μM) Poor fit(0.01-1 μM) 55 0.384 48% (0.01-1 μM) 0.780 (0.01-1 μM) 561.67 NE (0.01-1 μM) NE (0.01-1 μM) 57 10 NE (0.01-1 μM) NE (0.01-1 μM)58 4.81 NE (0.01-1 μM) NE (0.01-1 μM) 59 4.4 poor fit(0.01-0.3 μM) poorfit(0.01-0.3 μM) 60 0.321 0.247(0.01-0.3 uM) poor fit(0.01-0.3 μM) 610.037 0.751(0.01-0.3 μM) 1.05 (0.01-0.3 μM) 62 0.177 81% (10 μM) 0.413(0.3-10 μM) 63 0.213 53% (10 μM) 3.5 (0.3-10 μM) 64 0.36 4.06 (0.3-10μM) 1.72 (0.3-10 μM) 65 0.225 58% (10 μM) 8.6 (0.3-10 μM) 66 0.049 10(0.3-10 μM) 1.3 (0.3-10 μM) 67 0.166 NE (10 μM) NE (10 μM) 68 0.109 10(0.3-10 μM) 4.6 (0.3-10 μM) 69 1.43 53% (10 μM) 29% (10 μM) 70 0.871 41%(10 μM) NE (10 μM) 71 0.422 5.83 (0.01-1 μM) poor fit(0.01-1 μM) 72 2.4poor fit(0.01-1 μM) poor fit(0.01-1 μM) 73 8.16 poor fit(0.01-1 μM) poorfit(0.01-1 μM) 74 0.488 36% (10 μM) 44% (10 μM) 75 2.060 9.8 (0.3-10 μM)4.2 (0.3-10 μM) 76 0.151 >1 (0.01-1 μM) NE (0.01-1 μM) 77 10 >1 (0.01-1μM) NE (0.01-1 μM) 78 0.234 58% (0.01-1 μM) NE (0.01-1 μM) 79 1.33 29%(10 μM) 3.6 (0.3-10 μM) 80 0.333 NE (10 μM) 28% (10 μM) 81 0.201 6.7(0.3-10 μM) 2.8 (0.3-10 μM) 82 3.26 poor fit(0.01-0.3 μM) poorfit(0.01-0.3 μM) 83 0.049 poor fit(0.01-0.3 μM) poor fit(0.01-0.3 μM) 840.362 39% (0.01-1 μM) NE (0.01-1 μM) 85 6.48 45% (0.01-1 μM) NE (0.01-1μM) 86 1.3 28% (0.01-1 μM) NE (0.01-1 μM) 87 6.2 poor fit(0.01-0.3 μM)poor fit(0.01-0.3 μM) 88 2.17 0.349 (0.01-0.3 μM) poor fit(0.01-0.3 μM)89 0.205 0.517 (0.01-0.3 μM) poor fit(0.01-0.3 μM) 90 0.12 poorfit(0.01-0.3 μM) poor fit(0.01-0.3 μM) 91 1.43 58% (10 μM) 62% (10 μM)92 0.041 0.253 (0.01-1 μM) 0.269 (0.01-1 μM) 93 0.15 6.5 (0.3-10 μM) 1.8(0.3-10 μM) 94 0.551 NE (0.01-1 μM) NE (0.01-1 μM) 95 10 NE (0.01-1 μM)NE (0.01-1 μM) 96 0.768 10 (0.3-10 μM) 5.4 (0.3-10 μM) 97 0.515 NE (10μM) 3.08 (0.3-10 μM) 98 0.692 9.02 (0.3-10 μM) 3.6 (0.3-10 μM) 99 10.9NE (0.01-1 μM) NE (0.01-1 μM) 100 10 10 (0.3-10 μM) 10 (0.3-10 μM) 1013.58 >1 (0.01-1 μM) NE (0.01-1 μM) 102 0.037 48% (10 μM) 1.74 (0.3-10μM) 103 0.367 4.3 (0.3-10 μM) 31% (10 μM) 104 0.464 NE (10 μM) NE (10μM) 105 0.3 8.3 (0.3-10 μM) 3.82 (0.3-10 μM) 0.964(0.01-1 μM) NE (0.01-1μM) 106 0.148 71% (10 μM) 5.03 (0.3-10 μM) 107 0.43 3.53(0.3-10 μM) 2.42(0.3-10 μM) 108 0.394 5.8 (0.3-10 μM) 7.4 (0.3-10 μM) 109 0.322 4.5(0.3-10 μM) 7.9 (0.3-10 μM) 110 0.385 44% (10 μM) 30% (10 μM) 111 0.25762% (10 uM) 2.5 (0.3-10 μM) 112 0.041 2.5 (0.3-10 μM) 3 (0.3-10 μM) 1130.083 4.4 (0.3-10 μM) 7.8 (0.3-10 μM) 114 0.607 0.668 (0.01-1 μM) >1(0.01-1 μM) 115 0.731 NE (10 μM) NE (10 μM) 116 1.37 >1 (0.01-1 μM) >1(0.01-1 μM) 117 1.44 40% (10 μM) 25% (10 μM) 118 0.15 8.1 (0.3-10 μM) 10(0.3-10 μM) 119 1.29 28% (10 μM) NE (10 μM) 120 0.108 1.6 (0.3-10 μM)9.1 (0.3-10 μM) 121 0.233 6.6 (0.3-10 μM) 3.3 (0.3-10 μM) 122 3.010 NE(0.01-1 μM) NE (0.01-1 μM) 123 0.129 0.468 (0.01-1 μM) >1 (0.01-1 μM)124 0.103 2.5 (0.3-10 μM) 1.6 (0.3-10 μM) 125 0.313 2.1 (0.3-10 μM) 2.3(0.3-10 μM) 126 0.234 29% (10 μM) 1.9 (0.3-10 μM)

In Vivo Assays Example 3 Complete Freud's Adjuvant (CFA) InducedMechanical Allodynia

Animals arrived and were acclimatized for 1-2 weeks in atemperature-controlled room with a 12 h light/dark cycle and allowedfree access to standard laboratory chow and water.

CFA (Sigma) was injected intra-plantar (75 μg/150 μL) from aconcentration of 1:1 (diluted 1 mg/mL of CFA in 1 mL of PBS).CFA-induced mechanical allodynia was quantified by a Von frey test onday 2 (48 h post injection of CFA) and animals were randomized based oniPWT response (Dixon 1980). Animals exhibiting a PWT of <5.0 g wereselected for testing. Animals were administered a compound of Formula(I) through appropriate route based on their pharmacokinetic properties.Responses were measured with a Von-Frey filament. The maximum possibleeffect (% MPE) was determined as 100% if sensitivity in ipsilateral pawneared that of the contralateral paw. Values from the vehicle-treatedanimals were considered 0%. The compound effect was determined based onthese values. Resultant data are reported in Table 10, hereinbelow.

Example 4 Sciatic Nerve Ligation Model of Neuropathic Pain

Left L5 and L6 spinal nerves are isolated adjacent to the vertebralcolumn and were ligated with 5-0 silk suture distal to the dorsal rootganglion, as described by Kim and Chung (1992). The incision was closedwith the help of GLUture topical tissue adhesive. At 14 dayspost-surgery (one day prior to test compound administration), mechanicalallodynia was quantified using eight von Frey filaments, calibrated inthe range 0.4-15.1 g (Nielsen et al 2005). Rats were placed intoindividual plastic containers on top of a suspended wire mesh grid andacclimated to the test chambers for at least 15 min. Filaments wereapplied perpendicular to the mid-plantar paw surface, with enough forceto cause slight buckling, and held in place for 6-8 sec until a responsewas noted as a sharp paw withdrawal, flinching, licking and/or bitingimmediately upon removal of the filament (Nielsen et al 2005). Ratsexhibiting increased mechanical sensitivity (ipsilateral paw withdrawaltest cut-off of <4.0 g) were selected and randomized. Test compounds ofFormula (I) were administered and a response was measured at Tmax. Themaximum possible effect (% MPE) was determined to be 100% if thesensitivity in the ipsilateral paw neared that of the contralateral paw.Values from vehicle-treated animals were considered 0%. The compoundeffect was determined based on these values. Resultant data are reportedin Table 10, hereinbelow.

References

Dai, G, Haedo R J, Warren V A, Ratliff K S, Bugianesi R M, Rush A, etal: A high-throughput assay for evaluating state-dependence and subtypeselectivity of CaV2 calcium channel inhibitors. Assay Drug Dev Technol,2008, 6, 195-212.

Beladredetti F, Tringham E, Eduljee C, Jiang X, Dong H, Hendricson A, etal. “A fluorescence-based high throughput screening assay for theidentification of T-type calcium channel blockers”. Assay and DrugDevelopment Technologies, 2009, 7, 266-280.

Dixon,W J, “Efficient analysis of experimental observations”. Ann. Rev.Pharmacol. Toxicol., 1980, 20, 441-462.

Finley F A, Lubin M L, Neeper M P, Beck E, Liu Y, Flores C M, Qin N. “Anintegrated multiassay approach to the discovery of small-molecule N-typevoltage-gated calcium channel antagonists”. Assay and Drug DevelopmentTechnologies, 2010; 8(6), 685-694.

Kim, S H and Chung, J M., “An Experimental Model For PeripheralNeuropathy Produced By Segmental Spinal Nerve Ligation In The Rat”.Pain, 1992, 50, 355-363.

Nielsen C K, Lewis R J, Alewood D, Drinkwater R, Palant E, Patterson M,Yaksh T L, McCumber D and Smith M T. “Anti-allodynic efficacy of thec-conopeptide, Xen2174, in rats with neuropathic pain”. Pain, 2005,1-13.

TABLE 10 CFA and SNL In Vivo Data Dose CFA (% Reversal) SNL (% MPE)(mg/kg) Cpd 1 Cpd 11 Cpd 1 Cpd 11 Cpd 10 Cpd 38 3 NA 20.97 ± 7.88 NA 28.29 ± 10.84 12.17 ± 11.24 NA 10 NA 41.12 ± 5.14 NA 49.01 ± 9.93 40.53± 13.64 NA 12.5 19.73 ± 8.25 NA 22.21 ± 7.61  NA NA NA 25 37.62 ± 7.17NA  40.9 ± 20.29 NA NA NA 30 NA  55.8 ± 11.32 NA 70.69 ± 10.3 54.59 ±13.37 NA 50  58.8 ± 10.22 NA 64.07 ± 12.31 NA NA 87.01 ± 9.25 60 NA 76.4 ± 3.78 NA 96.18 ± 3.22 NA NA 100 75.26 ± 8.96 NA   75 ± 13.01 NA85.45 ± 8.44  NA

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

We claim:
 1. A substituted imidazole selected from the group consistingof: a compound according to structure 1

wherein structure 1 is4-[2-(2-Methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]-benzonitrile,a compound according to structure 11

wherein structure 11 is3-[1-(4-Chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine,a compound according to structure 38

wherein structure 38 is1-(4-Chlorophenyl)-2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole,a compound according to structure 51

wherein structure 51 is3-[1-(4-Chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-ethoxypyridine,a compound according to structure 92

wherein structure 92 is3-[5-Chloro-1-(4-fluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine,a compound according to structure 102

wherein structure 102 is4-[1-(4-Chlorophenyl)-2-(2-methoxyphenyl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol,and a compound according to structure 111

wherein structure 111 is4-[1-(3-Chloro-4-fluorophenyl)-2-(2-methoxyphenyl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol,and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 2. The substituted imidazole of claim 1, wherein thesubstituted imidazole is4-[2-(2-Methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]-benzonitrile,and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 3. The substituted imidazole of claim 1, wherein thesubstituted imidazole is3-[1-(4-Chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine,and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 4. The substituted imidazole of claim 1, wherein thesubstituted imidazole is1-(4-Chlorophenyl)-2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole,and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 5. The substituted imidazole of claim 1, wherein thesubstituted imidazole is3-[1-(4-Chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-ethoxypyridine,and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 6. The substituted imidazole of claim 1, wherein thesubstituted imidazole is3-[5-Chloro-1-(4-fluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine,and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 7. The substituted imidazole of claim 1, wherein thesubstituted imidazole is4-[1-(4-Chlorophenyl)-2-(2-methoxyphenyl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol,and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 8. The substituted imidazole of claim 1, wherein thesubstituted imidazole is4-[1-(3-Chloro-4-fluorophenyl)-2-(2-methoxyphenyl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol,and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 9. A pharmaceutical composition, comprising: a) at least one ofa substituted imidazole selected from the group consisting of: acompound according to structure 1

wherein structure 1 is4-[2-(2-Methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]-benzonitrile,a compound according to structure 11

wherein structure 11 is3-[1-(4-Chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine,a compound according to structure 38

wherein structure 38 is1-(4-Chlorophenyl)-2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole,a compound according to structure 51

wherein structure 51 is3-[1-(4-Chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-ethoxypyridine,a compound according to structure 92

wherein structure 92 is3-[5-Chloro-1-(4-fluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine,a compound according to structure 102

wherein structure 102 is4-[1-(4-Chlorophenyl)-2-(2-methoxyphenyl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol,and a compound according to structure 111

wherein structure 111 is4-[1-(3-Chloro-4-fluorophenyl)-2-(2-methoxyphenyl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol,and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof; and b) at least one of pharmaceutically acceptable carrier, apharmaceutically acceptable excipient and a pharmaceutically acceptablediluent.
 10. The pharmaceutical composition of claim 9, wherein thesubstituted imidazole is4-[2-(2-Methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]-benzonitrile,and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 11. The pharmaceutical composition of claim 9, wherein thesubstituted imidazole is3-[1-(4-Chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine,and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 12. The pharmaceutical composition of claim 9, wherein thesubstituted imidazole is1-(4-Chlorophenyl)-2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole,and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 13. The pharmaceutical composition of claim 9, wherein thesubstituted imidazole is3-[1-(4-Chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-ethoxypyridine,and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 14. The pharmaceutical composition of claim 9, wherein thesubstituted imidazole is 3-[5-Chloro-1-(4-fluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine, and enantiomers, diastereomers andpharmaceutically acceptable salts thereof.
 15. The pharmaceuticalcomposition of claim 9, wherein the substituted imidazole is4-[1-(4-Chlorophenyl)-2-(2-methoxyphenyl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol,and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 16. The pharmaceutical composition of claim 9, wherein thesubstituted imidazole is4-[1-(3-Chloro-4-fluorophenyl)-2-(2-methoxyphenyl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol,and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 17. A method of treating inflammatory pain, comprising:administrating to a patient a therapeutically effective amount of atleast one substituted imidazole selected from the group consisting of: acompound according to structure 1

wherein structure 1 is4-[2-(2-Methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]-benzonitrile,a compound according to structure 11

wherein structure 11 is3-[1-(4-Chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine,a compound according to structure 38

wherein structure 38 is1-(4-Chlorophenyl)-2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole,a compound according to structure 51

wherein structure 51 is3-[1-(4-Chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-ethoxypyridine,a compound according to structure 92

wherein structure 92 is3-[5-Chloro-1-(4-fluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine,a compound according to structure 102

wherein structure 102 is4-[1-(4-Chlorophenyl)-2-(2-methoxyphenyl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol,and a compound according to structure 111

wherein structure 111 is4-[1-(3-Chloro-4-fluorophenyl)-2-(2-methoxyphenyl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol,and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 18. The method of claim 17, wherein the inflammatory pain isdue to at least one of inflammatory bowel disease, irritable bowelsyndrome, visceral pain, migraine, post-operative pain, osteoarthritis,rheumatoid arthritis, back pain, lower back pain, joint pain, abdominalpain, chest pain, labor pain, musculoskeletal diseases, skin diseases,toothache, pyresis, bum, sunburn, snake bite, venomous snake bite,spider bite, insect sting, neurogenic/overactive bladder, interstitialcystitis, urinary tract infection, rhinitis, contactdermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis,enteritis, cholecystitis, pancreatitis, postmastectomy pain syndrome,menstrual pain, endometriosis pain, pain due to physical trauma,headache, sinus headache, tension headache and arachnoiditis.
 19. Themethod of claim 17, wherein the substituted imidazole is4-[2-(2-Methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 1-yl]-benzonitrile, and enantiomers, diastereomers andpharmaceutically acceptable salts thereof.
 20. The method of claim 17,wherein the substituted imidazole is3-[1-(4-Chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine,and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 21. The method of claim 17, wherein the substituted imidazoleis1-(4-Chlorophenyl)-2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole,and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 22. The method of claim 17, wherein the substituted imidazoleis3-[1-(4-Chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-ethoxypyridine, and enantiomers, diastereomers andpharmaceutically acceptable salts thereof.
 23. The method of claim 17,wherein the substituted imidazole is3-[5-Chloro-1-(4-fluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine,and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 24. The method of claim 17, wherein the substituted imidazoleis4-[1-(4-Chlorophenyl)-2-(2-methoxyphenyl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol,and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 25. The method of claim 17, wherein the substituted imidazoleis4-[1-(3-Chloro-4-fluorophenyl)-2-(2-methoxyphenyl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol,and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 26. A method of treating neuropathic pain, comprising:administrating to a patient a therapeutically effective amount of atleast one substituted imidazole selected from the group consisting of: acompound according to structure 1

wherein structure 1 is4-[2-(2-Methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]-benzonitrile,a compound according to structure 11

wherein structure 11 is3-[1-(4-Chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine,a compound according to structure 38

wherein structure 38 is1-(4-Chlorophenyl)-2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole,a compound according to structure 51

wherein structure 51 is3-[1-(4-Chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-ethoxypyridine,a compound according to structure 92

wherein structure 92 is3-[5-Chloro-1-(4-fluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine,a compound according to structure 102

wherein structure 102 is4-[1-(4-Chlorophenyl)-2-(2-methoxyphenyl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol,and a compound according to structure 111

wherein structure 111 is4-[1-(3-Chloro-4-fluorophenyl)-2-(2-methoxyphenyl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol,and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 27. The method of claim 26, wherein the neuropathic pain is atleast one of cancer pain, pain associated with neurological disorders,spine and peripheral nerve surgery pain, brain tumor induced pain, painassociated with traumatic brain injury (TBI), chemotherapy-induced pain,pain chronification, radicular pain, HIV pain, pain associated withspinal cord trauma, pain associated with chronic pain syndrome, painassociated with fibromyalgia, pain associated with chronic fatiguesyndrome, pain associated with lupus, pain associated with sarcoidosis,pain associated with peripheral neuropathy, pain associated withbilateral peripheral neuropathy, pain associated with diabeticneuropathy, central pain, neuropathies associated with spinal cordinjury, pain associated with stroke, pain associated with amyotrophiclateral sclerosis, pain associated with Parkinson's disease, painassociated with multiple sclerosis, pain associated with sciaticneuritis, pain associated with mandibular joint neuralgia, painassociated with peripheral neuritis, pain associated with polyneuritis,stump pain, phantom limb pain, pain associated with bony fractures, oralneuropathic pain, Charcot's pain, pain associated with complex regionalpain syndrome I and II (CRPS I/II), pain associated with radiculopathy,pain associated with Guillain-Barre syndrome, pain associated withmeralgia paresthetica, pain associated with burning-mouth syndrome, painassociated with optic neuritis, pain associated with postfebrileneuritis, pain associated with migrating neuritis, pain associated withsegmental neuritis, pain associated with Gombault's neuritis, painassociated with neuronitis, cervicobrachial neuralgia, cranialneuralgia, geniculate neuralgia, glossopharyngial neuralgia, migrainousneuralgia, idiopathic neuralgia, intercostals neuralgia, mammaryneuralgia, Morton's neuralgia, nasociliary neuralgia, occipitalneuralgia, postherpetic neuralgia, causalgia, red neuralgia, Sluder'sneuralgia, splenopalatine neuralgia, supraorbital neuralgia, trigeminalneuralgia, vulvodynia, and vidian neuralgia.
 28. The method of claim 26,wherein the substituted imidazole is4-[2-(2-Methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol- 1-yl]-benzonitrile, and enantiomers, diastereomers andpharmaceutically acceptable salts thereof.
 29. The method of claim 26,wherein the substituted imidazole is3-[1-(4-Chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine,and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 30. The method of claim 26, wherein the substituted imidazoleis1-(4-Chlorophenyl)-2-(2-methoxyphenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazole,and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 31. The method of claim 26, wherein the substituted imidazoleis3-[1-(4-Chlorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-ethoxypyridine,and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 32. The method of claim 26, wherein the substituted imidazoleis3-[5-Chloro-1-(4-fluorophenyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl]-2-methoxypyridine,and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 33. The method of claim 26, wherein the substituted imidazoleis4-[1-(4-Chlorophenyl)-2-(2-methoxyphenyl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol,and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 34. The method of claim 26, wherein the substituted imidazoleis4-[1-(3-Chloro-4-fluorophenyl)-2-(2-methoxyphenyl)-1H-imidazol-4-yl]-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol,and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.